Pyrrolo[2,3-d]pyrimidine compounds

ABSTRACT

Described herein are pyrrolo[2,3-d]pyrimidine compounds, their use as Janus Kinase (JAK) inhibitors, pharmaceutical compositions containing these compounds, and methods for their preparation.

FIELD OF THE INVENTION

The present invention provides pharmaceutically activepyrrolo[2,3-d]pyrimidine compounds and analogues. Such compounds areuseful for inhibiting Janus Kinase (JAK). This invention also isdirected to compositions comprising methods for making such compounds,and methods for treating and preventing conditions mediated by JAK.

BACKGROUND OF THE INVENTION

Protein kinases are families of enzymes that catalyze thephosphorylation of specific residues in proteins, broadly classifiedinto tyrosine and serine/threonine kinases. Inappropriate kinaseactivity, arising from mutation, overexpression, or inappropriateregulation, dysregulation or deregulation, as well as over or underproduction of growth factors or cytokines has been implicated in manydiseases, including but not limited to cancer, cardiovascular diseases,allergies, asthma and other respiratory diseases, autoimmune diseases,inflammatory diseases, bone diseases, metabolic disorders, andneurological and neurodegenerative disorders such as Alzheimer'sdisease. Inappropriate kinase activity triggers a variety of biologicalcellular responses relating to cell growth, cell differentiation,survival, apoptosis, mitogenesis, cell cycle control, and cell mobilityimplicated in the aforementioned and related diseases.

Thus, protein kinases have emerged as an important class of enzymes astargets for therapeutic intervention. In particular, the JAK family ofcellular protein tyrosine kinases (Jak1, Jak2, Jak3, and Tyk2) play acentral role in cytokine signaling (Kisseleva et al, Gene, 2002, 285, 1;Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to theirreceptors, cytokines activate JAK which then phosphorylate the cytokinereceptor, thereby creating docking sites for signaling molecules,notably, members of the signal transducer and activator of transcription(STAT) family that ultimately lead to gene expression. Numerouscytokines are known to activate the JAK family. These cytokines include,the IFN family (IFN-alpha, IFN-beta, IFN-omega, Limitin, IFN-gamma,IL-10, IL-19, IL-20, IL-22), the gp130 family (IL-6, IL-11, OSM, LIF,CNTF, NNT-1/BSF-3, G-CSF, CT-1, Leptin, IL-12, IL-23), gammaC family(IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), IL-3 family (IL-3,IL-5, GM-CSF), single chain family (EPO, GH, PRL, TPO), receptortyrosine kinases (EGF, PDGF, CSF-1, HGF), and G-protein coupledreceptors (AT1).

There remains a need for alternative compounds that effectively inhibitJAK enzymes, including JAK1, JAK2, JAK3, and/or Tyk2.

SUMMARY OF THE INVENTION

This invention is directed, in part, to compounds that generally fallwithin the structure of Formula I:

or a pharmaceutically acceptable salt thereof; wherein:

R¹ is selected from the group consisting of hydrogen and (C₁-C₆)alkyl;and

-   -   when R¹ is hydrogen, then R² is selected from the group        consisting of (C₅-C₆)alkyl, halo(C₁-C₆)alkyl,        (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₅-C₆)alkyl,        (C₁-C₆)alkenyl, halo(C₁-C₆)alkenyl, phenyl, phenyl(C₁-C₆)alkyl,        (C₃-C₆)cycloalkl, heterocyclyl, and heterocyclyl(C₁-C₆)alkyl;    -   when R¹ is (C₁-C₆)alkyl, then R² is selected from the group        consisting of (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,        (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,        (C₁-C₆)alkenyl, phenyl, phenyl(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,        heterocyclyl, and heterocyclyl(C₁-C₆)alkyl;    -   wherein (C₃-C₆)cycloalkyl, wherever it occurs, is optionally        substituted with one or more substituents selected from the        group consisting of hydroxy(C₁-C₆)alkyl, phenyl,        phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino; and wherein        when R¹ is hydrogen and R² is cyclobutyl, then the cyclobutyl is        substituted with one or more substituents selected from the        group consisting of hydroxy(C₁-C₆)alkyl, phenyl, halophenyl,        phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino;    -   wherein phenyl, wherever it occurs, is optionally substituted        with one or more substituents independently selected from the        group consisting of cyano, halo, hydroxy, (C₁-C₆)alkyl,        halo(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl, (C₁-C₆)alkoxy,        aminosulfonyl, and (C₁-C₆)alkylaminosulfonyl;    -   wherein heterocyclyl, wherever it occurs, is optionally        substituted with one or more substituents independently selected        from the group consisting of halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,        amino, and (C₁-C₆)alkylamino; and    -   wherein the (C₁-C₆)alkyl in phenyl(C₁-C₆)alkyl and        heterocyclyl(C₁-C₆)alkyl is optionally substituted with one more        substituents independently selected from the group consisting of        halo and hydroxy; and

R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

DETAILED DESCRIPTION

The invention will be more carefully understood from the followingdescription given by way of example only. The present invention isdirected to a class of pyrrolo[2,3-d]pyrimidine compounds. Inparticular, the present invention is directed topyrrolo[2,3-d]pyrimidine compounds useful as inhibitors of JAK. Whilethe present invention is not so limited, an appreciation of variousaspects of the invention will be gained through the following discussionand the examples provided below.

DEFINITIONS

The following is a list of definitions of various terms used herein:

The symbol

represents the point of attachment.

The term “alkyl” refers to a hydrocarbon radical having a straight orbranched chain or combinations thereof. Alkyl radicals can be aunivalent, a bivalent or a cyclic radical. Examples of univalent alkylradicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, pentyl, neopentyl, hexyl, isohexyl, and the like.Examples of bivalent alkyl radicals include

and the like. Examples of cyclic alkyl radicals include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term “alkoxy” means alkyl-O—, wherein alkyl is as defined above.Examples of such a substituent include methoxy (CH₃—O—), ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy andthe like.

The term “cycloalkyl” means a saturated carbocyclyl substituentcontaining from 3 to about 20 carbon atoms, preferably containing from 3to 8 carbon atoms. A cycloalkyl may be a single cyclic ring or multiplecondensed rings. Such cycloalkyl groups include, by way of example,single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl,cyclooctyl, and the like, or multiple ring structures such asadamantanyl, and the like.

The term “aryl” means an aromatic carbocyclyl containing from 6 to 14carbon ring atoms. The term aryl embraces both single and multiplerings. Examples of aryls include phenyl, naphthalenyl, and indenyl, andthe like.

The term “arylalkyl” means alkyl substituted with aryl, wherein alkyland aryl are as defined above.

The term alkylamino” means an alkyl substituted amino. The term embracesboth monoalkyl and dialkyl substitution.

The term “carboxy” means OH—C(O)—, which also may be depicted as:

The symbol “C(O)” represents carbonyl which also may be depicted as:

The term “oxo” means a double bonded oxygen, and may be depicted as ═O.

The term “hydroxy” or “hydroxyl” means OH—.

The term “hydroxyalkyl” means alkyl substituted with one more hydroxy,wherein hydroxy and alkyl are as defined above.

The term “halo” refers to bromo, chloro, fluoro or iodo.

The term “oxy” means an ether substituent, and may be depicted as —O—.

The term “sulfonyl” means SO₂—.

The term “thio” means HS—.

The term “alkylthio” is an alkyl substituted thio, which is alsodepicted as:

wherein thio and alkyl are as defined above.

The term “hydroxyalkyl” is a hydroxy substituted alkyl, examples includehydroxymethyl, hydroxyethyl and the like.

The term “haloalkyl” is an alkyl substituted with one or more halo,examples include fluoromethyl, bromomethyl, thrifluoromethyl, and thelike.

The term “heterocyclyl” means an unsaturated, saturated or partiallysaturated ring structure containing a total of 3 to 14 ring atoms. Atleast one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, orsulfur), with the remaining ring atoms being independently selected fromthe group consisting of carbon, oxygen, nitrogen, and sulfur.

A heterocyclyl may be a single ring, which typically contains from 3 to7 ring atoms, more typically from 3 to 6 ring atoms, and even moretypically 5 to 6 ring atoms. A heterocyclyl may also be 2 or 3 fusedrings. Examples of heterocyclyls include azepanyl, diazepanyl,morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydropyranyl, benzodioxolyl, benzofuranyl, furyl, indolyl,indazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridazinyl,pyrimidinyl, pyrrolopyridinyl, pyrazolyl, pyrazinyl, pyridinyl,quinolinyl, tetrazolyl, thiazolidinyl, thiamorpholinyl, triazolyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, 2,7diazaspiro[4.5]decanyl andthe like.

If substituents are described as being “independently selected” from agroup, each substituent is selected independent of the other. Eachsubstituent therefore may be identical to or different from the othersubstituent(s).

The term “livestock” refers to animals reared or raised in anagricultural setting to make products such as food or fiber, or for itslabor. In some embodiments, livestock are suitable for consumption bymammals, for example humans. Examples of livestock animals includemammals, such as cattle, goats, horses, pigs, sheep, including lambs,and rabbits, as well as birds, such as chickens, ducks and turkeys.

The term “companion animal” refers to a pet or household animal.Examples of companion animals include but are not limited to dogs, cats,rodents including hamsters, guinea pigs, gerbils and the like, rabbits,ferrets and birds.

The phrase “therapeutically-effective” indicates the capability of anagent to prevent, or improve the severity of, the disorder, whileavoiding adverse side effects typically associated with alternativetherapies. The phrase “therapeutically-effective” is to be understood tobe equivalent to the phrase “effective for the treatment, prevention, oramelioration”, and both are intended to qualify the amount of each agentfor use in the combination therapy which will achieve the goal ofimprovement in the severity of cancer, cardiovascular disease, or painand inflammation and the frequency of incidence over treatment of eachagent by itself, while avoiding adverse side effects typicallyassociated with alternative therapies.

“Treating” or “treatment” means an alleviation of symptoms associatedwith a disease, disorder or condition, or halt of further progression orworsening of those symptoms. Depending on the disease and condition ofthe patient, the term “treatment” as used herein may include one or moreof curative, palliative and prophylactic treatment. Treatment can alsoinclude administering a pharmaceutical formulation of the presentinvention in combination with other therapies. The compounds of theinvention can also be administered in conjunction with other drugsand/or therapies.

Compounds of the Invention

Among its many embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I:

wherein:

R¹ is selected from the group consisting of hydrogen and (C₁-C₆)alkyl;and

-   -   when R¹ is hydrogen, then R² is selected from the group        consisting of (C₆-C₆)alkyl, halo(C₁-C₆)alkyl,        (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₅-C₆)alkyl,        (C₁-C₆)alkenyl, halo(C₁-C₆)alkenyl, phenyl, phenyl(C₁-C₆)alkyl,        (C₃-C₆)cycloalkyl, heterocyclyl, and heterocyclyl(C₁-C₆)alkyl;    -   when R¹ is (C₁-C₆)alkyl, then R² is, selected from the group        consisting of (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,        (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,        (C₁-C₆)alkenyl, phenyl, phenyl(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,        heterocyclyl, and heterocyclyl(C₁-C₆)alkyl;    -   wherein (C₃-C₆)cycloalkyl, wherever it occurs, is optionally        substituted with one or more substituents selected from the        group consisting of hydroxy(C₁-C₆)alkyl, phenyl,        phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino; and wherein        when R¹ is hydrogen and R² is cyclobutyl, then the cyclobutyl is        substituted with one or more substituents selected from the        group consisting of hydroxy(C₁-C₆)alkyl, phenyl, halophenyl,        phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino;    -   wherein phenyl, wherever it occurs, is optionally substituted        with one or more substituents independently selected from the        group consisting of cyano, halo, hydroxy, (C₁-C₆)alkyl,        halo(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl, (C₁-C₆)alkoxy,        aminosulfonyl, and (C₁-C₆)alkylaminosulfonyl;    -   wherein heterocyclyl, wherever it occurs, is optionally        substituted with one or more substituents independently selected        from the group consisting of halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,        amino, and (C₁-C₆)alkylamino; and    -   wherein the (C₁-C₆)alkyl in phenyl(C₁-C₆)alkyl and        heterocyclyl(C₁-C₆)alkyl is optionally substituted with one more        substituents independently selected from the group consisting of        halo and hydroxy; and

R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is selected from the group consisting of hydrogen and (C₁-C₆)alkyl;and

-   -   when R¹ is hydrogen, then R² is selected from the group        consisting of (C₅-C₆)alkyl, halo(C₁-C₆)alkyl,        (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₆-C₆)alkyl,        halo(C₁-C₆)alkenyl, phenyl, phenyl(C₁-C₆)alkyl, cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, indolyl, indazolyl,        pyridinyl, pyrazolyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,        indolylmethyl, pyridinylmethyl, pyrimidinylmethyl,        pyrazinylmethyl, pyrazolylmethyl, tetrahydrofuranylmethyl, and        pyridinylethyl; and    -   when R¹ is (C₁-C₆)alkyl, then R² is selected from the group        consisting of (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,        hydroxy(C₁-C₆)alkyl, phenyl, phenyl(C₁-C₆)alkyl,        pyrazinylmethyl, and pyridinylmethyl;    -   wherein cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl,        wherever they occur, are optionally substituted with one or more        substituents selected from the group consisting of        hydroxy(C₁-C₆)alkyl, phenyl, phenyl(C₁-C₆)alkyl, and        (C₁-C₆)alkoxycarbonylamino; and wherein when R¹ is hydrogen and        R² is cyclobutyl, then the cyclobutyl is substituted with one or        more substituents selected from the group consisting of        hydroxy(C₁-C₆)alkyl, phenyl, phenyl(C₁-C₆)alkyl, and        (C₁-C₆)alkoxycarbonylamino;    -   wherein phenyl, wherever it occurs, is optionally substituted        with one or more substituents independently selected from the        group consisting of cyano, halo, hydroxy, (C₁-C₆)alkyl,        halo(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl, (C₁-C₆)alkoxy, and        aminosulfonyl;    -   wherein indolyl, indazolyl, pyridinyl, pyrimidinyl, pyrazinyl,        pyrazolyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, and        tetrahydrofuranyl, wherever they occur, are optionally        substituted with one or more substituents independently selected        from the group consisting of halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,        and amino; and    -   wherein the (C₁-C₆)alkyl in phenyl(C₁-C₆)alkyl is optionally        substituted with one more substituents independently selected        from the group consisting of halo and hydroxy; and

R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is hydrogen;

R² is selected from the group consisting of (C₅-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₅-C₆)alkyl,(C₁-C₆)alkenyl, and halo(C₁-C₆)alkenyl;

-   -   wherein the (C₃-C₆)cycloalkyl in (C₃-C₆)cycloalkyl(C₁-C₆)alkyl        is optionally substituted with one or more substituents selected        from the group consisting of hydroxy(C₁-C₆)alkyl, phenyl,        halophenyl, phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino;        and

R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is hydrogen;

R² is selected from the group consisting of (C₅-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₅-C₆)alkyl,(C₁-C₆)alkenyl, and halo(C₁-C₆)alkenyl;

-   -   wherein the (C₃-C₆)cycloalkyl in (C₃-C₆)cycloalkyl(C₁-C₆)alkyl        is optionally substituted with one or more substituents selected        from the group consisting of hydroxy(C₁-C₆)alkyl, phenyl,        halophenyl, phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino;        and

R³ selected from the group consisting of hydrogen and methyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is hydrogen;

R² is selected from the group consisting of cyclopropylmethyl andtrifluorobutenyl; and

R³ selected from the group consisting of hydrogen and methyl.

In one embodiment, the present invention includes compounds orpharmaceutically acceptable salts thereof, selected from the groupconsisting of

-   N-(cyclopropylmethyl)-1-{cis-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;    and-   1-{trans-4-[(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-(3,4,4-trifluorobut-3-en-1-yl)methanesulfonamide.

In one embodiment, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein

R¹ is (C₁-C₆)alkyl;

R² is selected from the group consisting of (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkenyl, and halo(C₁-C₆)alkenyl;

-   -   wherein the (C₃-C₆)cycloalkyl in (C₃-C₆)cycloalkyl(C₁-C₆)alkyl        is optionally substituted with one or more substituents selected        from the group consisting of hydroxy(C₁-C₆)alkyl, phenyl,        halophenyl, phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino;        and

R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

In some embodiments, the present, invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is (C₁-C₆)alkyl;

R² is selected from the group consisting of (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, andhydroxy(C₁-C₆)alkyl;

-   -   wherein the (C₃-C₆)cycloalkyl in (C₃-C₆)cycloalkyl(C₁-C₆)alkyl        is optionally substituted with one or more substituents selected        from the group consisting of hydroxy(C₁-C₆)alkyl, phenyl,        halophenyl, phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino;        and

R³ selected from the group consisting of hydrogen and methyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is (C₁-C₆)alkyl;

R² is selected from the group consisting of (C₁-C₆)alkyl andhydroxy(C₁-C₆)alkyl; and

R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is methyl;

R² is selected from the group consisting of methyl and hydroxyethyl; and

R³ selected from the group consisting of hydrogen and methyl.

In one embodiment, the present invention includes compounds orpharmaceutically acceptable salts thereof, selected from the groupconsisting of

-   N-(2-hydroxyethyl)-N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[(6-aminopyridin-2-yl)methyl]-N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-(pyridin-3-ylmethyl)methanesulfonamide;-   N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-(pyrazin-2-ylmethyl)methanesulfonamide;    and-   N,N-dimethyl((1r,4r)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide.

In one embodiment, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is selected from the group consisting of hydrogen and (C₁-C₆)alkyl;and

R² is selected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl;

-   -   wherein cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are        optionally substituted with one or more substituents selected        from the group consisting of hydroxy(C₁-C₆)alkyl, phenyl,        halophenyl, phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino;        and    -   wherein when R¹ is hydrogen and R² is cyclobutyl, then the        cyclobutyl is substituted with one or more substituents selected        from the group consisting of hydroxy(C₁-C₆)alkyl, phenyl,        halophenyl, phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino;        and

R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is selected from the group consisting of hydrogen and (C₁-C₆)alkyl;and

R² is selected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl;

-   -   wherein cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are        optionally substituted with one or more substituents selected        from the group consisting of hydroxypropyl, phenyl,        fluorophenyl, phenylmethyl and tert-butoxycarbonylamino; and    -   wherein when R¹ is hydrogen and R² is cyclobutyl, then the        cyclobutyl is substituted with one or more substituents selected        from the group consisting of hydroxypropyl, phenyl,        fluorophenyl, phenylmethyl and tert-butoxycarbonylamino; and

R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein R¹ is hydrogen.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein R¹ is (C₁-C₆)alkyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is selected from the group consisting of hydrogen and methyl; and

R² is selected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl;

-   -   wherein cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are        optionally substituted with one or more substituents selected        from the group consisting of hydroxypropyl, phenyl,        fluorophenyl, phenylmethyl and tert-butoxycarbonylamino; and    -   wherein when R¹ is hydrogen and R² is cyclobutyl, then the        cyclobutyl is substituted with one or more substituents selected        from the group consisting of hydroxypropyl, phenyl,        fluorophenyl, phenylmethyl and tert-butoxycarbonylamino; and

R³ selected from the group consisting of hydrogen and methyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is hydrogen;

R² is selected from the group consisting of cyclopropyl,fluorophenylcyclopentyl, hydroxypropylcyclohexyl, andtert-butoxycarbonylaminocyclobutyl; and

R³ selected from the group consisting of hydrogen and methyl.

In one embodiment, the present invention includes compounds orpharmaceutically acceptable salts thereof, selected from the groupconsisting of

-   N-cyclopropyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[trans-4-(1-hydroxy-1-methylethyl)cyclohexyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   tert-butyl    (3-{[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methyl)sulfonyl]amino}cyclobutyl)carbamate;-   N-[(1R,2R)-2-(4-fluorophenyl)cyclopentyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-(1-benzylcyclobutyl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;    and-   1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-[(1S,2R)-2-phenylcyclopropyl]methanesulfonamide.

In one embodiment, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is selected from the group consisting of hydrogen and (C₁-C₆)alkyl;

R² is selected from the group consisting of phenyl, phenyl(C₁-C₆)alkyl,heterocyclyl, and heterocyclyl(C₁-C₆)alkyl; and

-   -   wherein phenyl, wherever it occurs, is optionally substituted        with one or more substituents independently selected from the        group consisting of cyano, halo, hydroxy, (C₁-C₆)alkyl,        halo(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl, (C₁-C₆)alkoxy, and        aminosulfonyl;    -   wherein heterocyclyl, wherever it occurs, is optionally        substituted with one or more substituents independently selected        from the group consisting of halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,        and amino; and    -   wherein the (C₁-C₆)alkyl in phenyl(C₁-C₆)alkyl and        heterocyclyl(C₁-C₆)alkyl is optionally substituted with one more        substituents independently selected from the group consisting of        halo and hydroxy; and

R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is selected from the group consisting of hydrogen and (C₁-C₆)alkyl;

R² is selected from the group consisting of phenyl andphenyl(C₁-C₆)alkyl; and

-   -   wherein phenyl, wherever it occurs, is optionally substituted        with one or more substituents independently selected from the        group consisting of cyano, halo, hydroxy, (C₁-C₆)alkyl,        halo(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl, (C₁-C₆)alkoxy, and        aminosulfonyl; and    -   wherein the (C₁-C₆)alkyl in phenyl(C₁-C₆)alkyl is optionally        substituted with one more substituents independently selected        from the group consisting of halo and hydroxy; and

R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is selected from the group consisting of hydrogen and (C₁-C₆)alkyl;

R² is selected from the group consisting of phenyl andphenyl(C₁-C₄)alkyl;

-   -   wherein phenyl, wherever it occurs, is optionally substituted        with one or more substituents independently selected from the        group consisting of cyano, chloro, fluoro, hydroxy, methyl,        trifluoromethyl, cyanomethyl, methoxy, and aminosulfonyl; and    -   wherein the (C₁-C₄)alkyl in phenyl(C₁-C₄)alkyl is optionally        substituted with one more substituents independently selected        from the group consisting of fluoro and hydroxy; and

R³ is selected from the group consisting of hydrogen and methyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is selected from the group consisting of hydrogen and methyl;

R² is selected from the group consisting of phenyl andphenyl(C₁-C₄)alkyl;

-   -   wherein phenyl, wherever it occurs, is optionally substituted        with one or more substituents independently selected from the        group consisting of cyano, chloro, fluoro, hydroxy, methyl,        trifluoromethyl, cyanomethyl, methoxy, and aminosulfonyl; and    -   wherein the (C₁-C₄)alkyl in phenyl(C₁-C₄)alkyl is optionally        substituted with one more substituents independently selected        from the group consisting of fluoro and hydroxy; and

R³ is selected from the group consisting of hydrogen and methyl.

In one embodiment, the present invention includes compounds orpharmaceutically acceptable salts thereof, selected from the groupconsisting of

-   4-(2-{[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methyl)sulfonyl]amino}ethyl)benzenesulfonamide;-   N-[2-(4-hydroxyphenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[2-(2,4-dimethylphenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[2-(2-methoxyphenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-(2,2-difluoro-2-phenylethyl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[2-(4-methylphenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[2-fluoro-2-(4-fluorophenyl)propyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[2-fluoro-2-(3-fluorophenyl)propyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[2-(3-methoxyphenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[2-fluoro-2-(4-fluorophenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-{2-[4-(trifluoromethyl)phenyl]ethyl}methanesulfonamide;-   N-{2-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl}-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-(2-phenylethyl)methanesulfonamide;-   N-benzyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-(4-methoxybenzyl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[4-(cyanomethyl)phenyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-(4-cyanophenyl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[2-(4-chlorophenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[2-(2-fluorophenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[2-(3-fluorophenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[2-(3-chlorophenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[2-(2-fluoro-4-isopropylphenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[2-(3,4-difluorophenyl)-2-hydroxyethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[3-(2-methoxyphenyl)propyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[2-(3,4-dichlorophenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   1-{cis-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-(2-phenylethyl)methanesulfonamide;-   N-benzyl-1-{cis-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;    and-   N-(4-methoxybenzyl)-1-{cis-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is selected from the group consisting of hydrogen and (C₁-C₆)alkyl;

R² is selected from the group consisting of heterocyclyl andheterocyclyl(C₁-C₆)alkyl; and

-   -   wherein heterocyclyl, wherever it occurs, is optionally        substituted with one or more substituents independently selected        from the group consisting of halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,        and amino; and    -   wherein the (C₁-C₆)alkyl in heterocyclyl(C₁-C₆)alkyl is        optionally substituted with one more substituents independently,        selected from the group consisting of halo and hydroxy; and

R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is selected from the group consisting of hydrogen and (C₁-C₆)alkyl;

R² is selected from the group consisting of 3-12 membered ringheterocyclyl and 3-12 membered ring heterocyclyl(C₁-C₆)alkyl; and

-   -   wherein heterocyclyl, wherever it occurs, is optionally        substituted with one or more substituents independently selected        from the group consisting of halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,        and amino; and    -   wherein the (C₁-C₆)alkyl in heterocyclyl(C₁-C₆)alkyl is        optionally substituted with one more substituents independently        selected from the group consisting of halo and hydroxy; and

R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is selected from the group consisting of hydrogen and (C₁-C₆)alkyl;

R² is selected from the group consisting of indolyl, indazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, tetrahydrofuranyl,indolyl(C₁-C₆)alkyl, indazolyl(C₁-C₆)alkyl, pyridinyl(C₁-C₆)alkyl,pyrimidinyl(C₁-C₆)alkyl, pyrazinyl(C₁-C₆)alkyl, pyrazolyl(C₁-C₆)alkyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl(C₁-C₆)alkyl, andtetrahydrofuranyl(C₁-C₆)alkyl; and

-   -   wherein indolyl, indazolyl, pyridinyl, pyrimidinyl, pyrazinyl,        pyrazolyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,        tetrahydrofuranyl are optionally substituted with one or more        substituents independently selected from the group consisting of        halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, and amino; and    -   wherein the (C₁-C₆)alkyl in indolyl(C₁-C₆)alkyl,        indazolyl(C₁-C₆)alkyl, pyridinyl(C₁-C₆)alkyl,        pyrimidinyl(C₁-C₆)alkyl, pyrazinyl(C₁-C₆)alkyl,        pyrazolyl(C₁-C₆)alkyl,        3,4-dihydro-2H-benzo[b][1,4]dioxepinyl(C₁-C₆)alkyl, and        tetrahydrofuranyl(C₁-C₆)alkyl is optionally substituted with one        more substituents independently selected from the group        consisting of halo and hydroxy; and

R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is selected from the group consisting of hydrogen and (C₁-C₆)alkyl;

R² is selected from the group consisting of indolyl, indazolyl,pyridinyl, pyrazolyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,indolylmethyl, pyridinylmethyl, pyrimidinylmethyl, pyrazinylmethyl,pyrazolylmethyl, tetrahydrofuranylmethyl, and pyridinylethyl; and

-   -   wherein indolyl, indazolyl, pyridinyl, pyrimidinyl, pyrazinyl,        pyrazolyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, and        tetrahydrofuranyl are optionally substituted with one or more        substituents independently selected from the group consisting of        halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, and amino; and

R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

In some embodiments, the present invention includes compounds orpharmaceutically acceptable salts thereof, having a structure accordingto formula I, wherein:

R¹ is selected from the group consisting of hydrogen and methyl;

R² is selected from the group consisting of indolyl, indazolyl,pyridinyl, pyrazolyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,indolylmethyl, pyridinylmethyl, pyrimidinylmethyl, pyrazinylmethyl,pyrazolylmethyl, tetrahydrofuranylmethyl, and pyridinylethyl;

-   -   wherein indolyl, indazolyl, pyridinyl, pyrimidinyl, pyrazinyl,        pyrazolyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, and        tetrahydrofuranyl, are optionally substituted with one or more        substituents independently selected from the group consisting of        chloro, methyl, methoxy, and amino; and

R³ selected from the group consisting of hydrogen and methyl.

In one embodiment, the present invention includes compounds orpharmaceutically acceptable salts thereof, selected from the groupconsisting of

-   1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-(pyridin-3-ylmethyl)methanesulfonamide;-   1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-1H-pyrazol-5-ylmethanesulfonamide;-   N-(5-methyl-1H-pyrazol-3-yl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-1H-indol-5-yl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-(6-chloropyridin-3-yl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-1H-indazol-5-yl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-(6-methoxypyridin-3-yl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-(6-methylpyridin-3-yl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[(2-methyl-1H-indol-5-yl)methyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[(5-methylpyrazin-2-yl)methyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-[(2R)-tetrahydrofuran-2-ylmethyl]methanesulfonamide;-   N-[2-(6-methylpyridin-2-yl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;-   N-[(4,6-dimethylpyrimidin-2-yl)methyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;    and-   N-[(1,3-dimethyl-1H-pyrazol-4-yl)methyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide.

In one embodiment, the present invention includes a pharmaceuticalcomposition comprising a compound of Formula I or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the present invention includes a method for thetreatment of a Janus Kinase mediated condition in a subject in need ofsuch treatment, wherein the method comprises administering to thesubject an amount of a compound of Formula I or a pharmaceuticallyacceptable salt thereof, wherein the amount of the compound is effectivefor the treatment of the Janus Kinase mediated condition.

In one embodiment, the Janus Kinase mediated condition is Alzheimer'sdisease, arthritis, autoimmune thyroid disorders, cancer, diabetes,leukemia, T-cell prolymphocytic leukemia, lymphoma, myleoproliferationdisorders, lupus, multiple myeloma, multiple sclerosis, osteoarthritis,sepsis, prostate cancer, T-cell autoimmune disease, inflammatorydiseases, chronic and acute allograft transplant rejection, bone marrowtransplant, stroke, asthma, chronic obstructive pulmonary disease,allergy, bronchitis, viral diseases, or Type I diabetes andcomplications from diabetes.

In one embodiment, the Janus Kinase mediated condition is selected fromthe group consisting of asthma, Crohn's disease, dry eye, uveitis,inflammatory bowel disease, organ transplant rejection, psoriasis,rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis andulcerative colitis.

Pharmaceutically acceptable salts of the compounds of formula I includethe acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, adipate, aspartate, benzoate,besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate,citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate,gluconate, glucuronate, hexafluorophosphate, hibenzate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,isethionate, lactate, malate, maleate, malonate, mesylate,methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate,tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example,hemisulphate and hemicalcium salts. For a review on suitable salts, seeHandbook of Pharmaceutical Salts Properties, Selection, and Use by Stahland Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of formula I may beprepared by one or more of three methods: (i) by reacting the compoundof formula I with the desired acid or base; (ii) by removing an acid- orbase-labile protecting group from a suitable precursor of the compoundof formula I or by ring-opening a suitable cyclic precursor, forexample, a lactone or lactam, using the desired acid or base; or (iii)by converting one salt of the compound of formula I to another byreaction with an appropriate acid or base or by means of a suitable ionexchange column. All three reactions are typically carried out insolution. The resulting salt may precipitate out and be collected byfiltration or may be recovered by evaporation of the solvent. The degreeof ionisation in the resulting salt may vary from completely ionised toalmost non-ionised.

The compounds of the invention may exist in a continuum of solid statesranging from fully amorphous to fully crystalline. The term ‘amorphous’refers to a state in which the material lacks long range order at themolecular level and, depending upon temperature, may exhibit thephysical properties of a solid or a liquid. Typically such materials donot give distinctive X-ray diffraction patterns and, while exhibitingthe properties of a solid, are more formally described as a liquid. Uponheating, a change from solid to liquid properties occurs which ischaracterised by a change of state, typically second order (‘glasstransition’). The term ‘crystalline’ refers to a solid phase in whichthe material has a regular ordered internal structure at the molecularlevel and gives a distinctive X-ray diffraction pattern with definedpeaks. Such materials when heated sufficiently will also exhibit theproperties of a liquid, but the change from solid to liquid ischaracterised by a phase change, typically first order (‘meltingpoint’).

The compounds of the invention may also exist in unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm ‘hydrate’ is employed when said solvent is water.

A currently accepted classification system for organic hydrates is onethat defines isolated site, channel, or metal-ion coordinatedhydrates—see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed.H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones inwhich the water molecules are isolated from direct contact with eachother by intervening organic molecules. In channel hydrates, the watermolecules lie in lattice channels where they are next to other watermolecules. In metal-ion coordinated hydrates, the water molecules arebonded to the metal ion.

When the solvent or water is tightly bound, the complex will have awell-defined stoichiometry independent of humidity. When, however, thesolvent or water is weakly bound, as in channel solvates and hygroscopiccompounds, the water/solvent content will be dependent on humidity anddrying conditions. In such cases, non-stoichiometry will be the norm.

Also included within the scope of the invention are multi-componentcomplexes (other than salts and solvates) wherein the drug and at leastone other component are present in stoichiometric or non-stoichiometricamounts. Complexes of this type include clathrates (drug-host inclusioncomplexes) and co-crystals. The latter are typically defined ascrystalline complexes of neutral molecular constituents which are boundtogether through non-covalent interactions, but could also be a complexof a neutral molecule with a salt. Co-crystals may be prepared by meltcrystallisation, by recrystallisation from solvents, or by physicallygrinding the components together—see Chem Commun, 17, 1889-1896, by O.Almarsson and M. J. Zaworotko (2004). For a general review ofmulti-component complexes, see J Pharm Sci, 64 (8), 1269-1288, byHaleblian (August 1975).

The compounds of the invention may also exist in a mesomorphic state(mesophase or liquid crystal) when subjected to suitable conditions. Themesomorphic state is intermediate between the true crystalline state andthe true liquid state (either melt or solution). Mesomorphism arising asthe result of a change in temperature is described as ‘thermotropic’ andthat resulting from the addition of a second component, such as water oranother solvent, is described as ‘lyotropic’. Compounds that have thepotential to form lyotropic mesophases are described as ‘amphiphilic’and consist of molecules which possess an ionic (such as —COO⁻Na⁺,—COO⁻K⁺, or —SO₃ ⁻Na⁺) or non-ionic (such as —N⁻N⁺(CH₃)₃) polar headgroup. For more information, see Crystals and the Polarizing Microscopeby N. H. Hartshorne and A. Stuart, 4^(th) Edition (Edward Arnold, 1970).

Hereinafter all references to compounds of formula I include referencesto salts, solvates, multi-component complexes and liquid crystalsthereof and to solvates, multi-component complexes and liquid crystalsof salts thereof.

The compounds of the invention include compounds of formula I ashereinbefore defined, including all polymorphs and crystal habitsthereof, prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) as hereinafter defined and isotopically-labeledcompounds of formula I.

As indicated, so-called ‘prodrugs’ of the compounds of formula I arealso within the scope of the invention. Thus certain derivatives ofcompounds of formula I which may have little or no pharmacologicalactivity themselves can, when administered into or onto the body, beconverted into compounds of formula I having the desired activity, forexample, by hydrolytic cleavage. Such derivatives are referred to as‘prodrugs’. Further information on the use of prodrugs may be found inPro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T.Higuchi and W. Stella) and Bioreversible Carriers in Drug Design,Pergamon Press, 1987 (Ed. E. B. Roche, American PharmaceuticalAssociation).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormula I with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include: (i)where the compound of formula I contains a carboxylic acid functionality(—COOH), an ester thereof, for example, a compound wherein the hydrogenof the carboxylic acid functionality of the compound of formula (I) isreplaced by (C₁-C₈)alkyl; (ii) where the compound of formula I containsan alcohol functionality (—OH), an ether thereof, for example, acompound wherein the hydrogen of the alcohol functionality of thecompound of formula I is replaced by (C₁-C₆)alkanoyloxymethyl; and (iii)where the compound of formula I contains a primary or secondary aminofunctionality (—NH₂ or —NHR where R≠H), an amide thereof, for example, acompound wherein, as the case may be, one or both hydrogens of the aminofunctionality of the compound of formula I is/are replaced by(C₁-C₁₀)alkanoyl. Further examples of replacement groups in accordancewith the foregoing examples and examples of other prodrug types may befound in the aforementioned references. Moreover, certain compounds offormula I may themselves act as prodrugs of other compounds of formulaI.

Also included within the scope of the invention are metabolites ofcompounds of formula I, that is, compounds formed in vivo uponadministration of the drug. Some examples of metabolites in accordancewith the invention include: (i) where the compound of formula I containsa methyl group, an hydroxymethyl derivative thereof (—CH₃->-CH₂OH): (ii)where the compound of formula I contains an alkoxy group, an hydroxyderivative thereof (—OR->-OH); (iii) where the compound of formula Icontains a tertiary amino group, a secondary amino derivative thereof(—Na¹R²->-NHR¹ or —NHR²); (iv) where the compound of formula I containsa secondary amino group, a primary derivative thereof (—NHR¹->-NH₂); (v)where the compound of formula I contains a phenyl moiety, a phenolderivative thereof (-Ph->-PhOH); and (vi) where the compound of formulaI contains an amide group, a carboxylic acid derivative thereof(—CONH₂->COOH).

Compounds of formula I containing one or more asymmetric carbon atomscan exist as two or more stereoisomers. Where a compound of formula Icontains an alkenyl or alkenylene group, geometric cis/trans (or Z/E)isomers are possible. Where, structural isomers are interconvertible viaa low energy barrier, tautomeric isomerism (‘tautomerism’) can occur.This can take the form of proton tautomerism in compounds of formula Icontaining, for example, an imino, keto, or oxime group, or so-calledvalence tautomerism in compounds which contain an aromatic moiety. Itfollows that a single compound may exhibit more than one type ofisomerism.

Included within the scope of the present invention are allstereoisomers, geometric isomers and tautomeric forms of the compoundsof formula I, including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition or base salts wherein the counterion is optically active, forexample, d-lactate or l-lysine, or racemic, for example, dl-tartrate ordl-arginine.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallisation.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of formula I contains an acidic or basicmoiety, a base or acid, such as 1-phenylethylamine or tartaric acid. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50% byvolume of isopropanol, typically from 2% to 20%, and from 0 to 5% byvolume of an alkylamine, typically 0.1% diethylamine. Concentration ofthe eluate affords the enriched mixture.

When any racemate crystallises, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer. Whileboth of the crystal forms present in a racemic mixture have identicalphysical properties, they may have different physical propertiescompared to the true racemate. Racemic mixtures may be separated byconventional techniques known to those skilled in the art—see, forexample, Stereochemistry of Organic Compounds by E. L. Eliel and S. H.Wilen (Wiley, 1994).

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of formula I wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature. Examples of isotopes suitable for inclusion inthe compounds of the invention include isotopes of hydrogen, such as ²Hand ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl,fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as¹³N and ¹⁸N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P,and sulphur, such as ³⁵S Certain isotopically-labelled compounds offormula I, for example, those incorporating a radioactive isotope, areuseful in drug and/or substrate tissue distribution studies. Theradioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, areparticularly useful for this purpose in view of their ease ofincorporation and ready means of detection. Substitution with heavierisotopes such as deuterium, i.e. ²H, may afford certain therapeuticadvantages resulting from greater metabolic stability, for example,increased in vivo half-life or reduced dosage requirements, and hencemay be preferred in some circumstances. Substitution with positronemitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful inPositron Emission Topography (PET) studies for examining substratereceptor occupancy. Isotopically-labeled compounds of formula I cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in theaccompanying Examples and Preparations using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Also within the scope of the invention are intermediate compounds offormula I as hereinbefore defined, all salts, solvates and complexesthereof and all solvates and complexes of salts thereof as definedhereinbefore for compounds of formula I. The invention includes allpolymorphs of the aforementioned species and crystal habits thereof.

When preparing compounds of formula I in accordance with the invention,it is open to a person skilled in the art to routinely select the formof compound of formula I which provides the best combination of featuresfor this purpose. Such features include the melting point, solubility,processability and yield of the intermediate form and the resulting easewith which the product may be purified on isolation.

Pharmaceutical Compositions

Also provided are compositions which can be prepared by mixing one ormore compounds described herein, or pharmaceutically acceptable salts ortautomers thereof, with pharmaceutically acceptable carriers,excipients, binders, diluents or the like, to treat or ameliorate avariety of JAK related conditions. The pharmaceutical compositions ofthe instant invention can be manufactured by methods well known in theart such as conventional granulating, mixing, dissolving, encapsulating,lyophilizing, emulsifying or levigating processes, among others. Thecompositions can be in the form of, for example, granules, powders,tablets, capsule syrup, suppositories, injections, emulsions, elixirs,suspensions or solutions. The instant compositions can be formulated forvarious routes of administration, for example, by oral administration,transmucosal administration, rectal administration, topicaladministration or subcutaneous administration as well as intrathecal,intravenous, intramuscular, intraperitoneal, intranasal, intraocular orintraventricular injection. The compound or compounds of the instantinvention can also be administered in a local rather than a systemicfashion, such as injection as a sustained release formulation. Thefollowing dosage forms are given by way of example and should not beconstrued as limiting the instant invention.

For oral, buccal, and sublingual administration, powders, suspensions,granules, tablets, pills, capsules, gelcaps, and caplets are acceptableas solid dosage forms. These can be prepared, for example, by mixing oneor more compounds of the instant invention, or pharmaceuticallyacceptable salts or tautomers thereof, with at least one additive orexcipient such as a starch or other additive. Suitable additives orexcipients are sucrose, lactose, cellulose sugar, mannitol, maltitol,dextran, sorbitol, starch, agar, alginates, chitins, chitosans, pectins,tragacanth gum, gum arabic, gelatins, collagens, casein, albumin,synthetic or semi-synthetic polymers or glycerides, methyl cellulose,hydroxypropylmethyl-cellulose, and/or polyvinylpyrrolidone. Optionally,oral dosage forms can contain other ingredients to aid inadministration, such as an inactive diluent, or lubricants such asmagnesium stearate, or preservatives such as paraben or sorbic acid, oranti-oxidants such as ascorbic acid, tocopherol or cysteine, adisintegrating agent, binders, thickeners, buffers, sweeteners,flavoring agents or perfuming agents. Additionally, dyestuffs orpigments can be added for identification. Tablets and pills can befurther treated with suitable coating materials known in the art.

Liquid dosage forms for oral administration can be in the form ofpharmaceutically acceptable emulsions, syrups, elixirs, suspensions,slurries and solutions, which can contain an inactive diluent, such aswater. Pharmaceutical formulations can be prepared as liquid suspensionsor solutions using a sterile liquid, such as, but not limited to, anoil, water, an alcohol, and combinations of these. Pharmaceuticallysuitable surfactants, suspending agents, emulsifying agents, can beadded for oral or parenteral administration.

As noted above, suspensions can include oils. Such oils include, but arenot limited to, peanut oil, sesame oil, cottonseed oil, corn oil, oliveoil and mixtures of oils. Suspension preparation can also contain estersof fatty acids such as ethyl oleate, isopropyl myristate, fatty acidglycerides and acetylated fatty acid glycerides. Suspension formulationscan include alcohols, such as, but not limited to, ethanol, isopropylalcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, suchas but not limited to, poly(ethyleneglycol), petroleum hydrocarbons suchas mineral oil and petrolatum; and water can also be used in suspensionformulations.

The compounds may also be administered topically, (intra)dermally, ortransdermally to the skin or mucosa. Typical formulations for thispurpose include gels, hydrogels, lotions, solutions, creams, ointments,dusting powders, dressings, foams, films, skin patches, wafers,implants, sponges, fibres, bandages and microemulsions. Liposomes mayalso be used. Typical carriers include alcohol, water, mineral oil,liquid petrolatum, white petrolatum, glycerin, polyethylene glycol andpropylene glycol. Penetration enhancers may be incorporated-see, forexample, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October1999).

Other means of topical administration include delivery byelectroporation, iontophoresis, phonophoresis, sonophoresis andmicroneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

Formulations for topical administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

For nasal administration, the pharmaceutical formulations can be a sprayor aerosol containing and appropriate solvents and optionally othercompounds such as, but not limited to, stabilizers, antimicrobialagents, antioxidants, pH modifiers, surfactants, bioavailablitymodifiers and combinations of these. A propellant for an aerosolformulation can include compressed air, nitrogen, carbon dioxide, or ahydrocarbon based low boiling solvent. The compound or compounds of theinstant invention are conveniently delivered in the form of an aerosolspray presentation from a nebulizer or the like.

Injectable dosage forms generally include aqueous suspensions or oilsuspensions which can be prepared using a suitable dispersant or wettingagent and a suspending agent. Injectable forms can be in solution phaseor in the form of a suspension, which is prepared with a solvent ordiluent. Acceptable solvents or vehicles include sterilized water,Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils can be employed as solvents or suspendingagents. Generally, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the pharmaceutical formulation can be a powder suitablefor reconstitution with an appropriate solution as described above.Examples of these include, but are not limited to, freeze dried, rotarydried or spray dried powders, amorphous powders, granules, precipitates,or particulates. For injection, the formulations can optionally containstabilizers, pH modifiers, surfactants, bioavailability modifiers andcombinations of these. The compounds can be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection can be in ampoules or inmulti-dose containers.

For rectal administration, the pharmaceutical formulations can be in theform of a suppository, an ointment, an enema, a tablet or a cream forrelease of compound in the intestines, sigmoid flexure and/or rectum.Rectal suppositories are prepared by mixing one or more compounds of theinstant invention, or pharmaceutically acceptable salts or tautomers ofthe compound, with acceptable vehicles, for example, cocoa butter orpolyethylene glycol, which is present in a solid phase at normal storingtemperatures, and present in a liquid phase at those temperaturessuitable to release a drug inside the body, such as in the rectum. Oilscan also be employed in the preparation of formulations of the softgelatin type, and suppositories. Water, saline, aqueous dextrose andrelated sugar solutions, and glycerols can be employed in thepreparation of suspension formulations which can also contain suspendingagents such as pectins, carbomers, methyl cellulose, hydroxypropylcellulose or carboxymethyl cellulose, as well as buffers andpreservatives.

Besides those representative dosage forms described above,pharmaceutically acceptable excipients and carries are generally knownto those skilled in the art and are thus included in the instantinvention. Such excipients and carriers are described, for example, in“Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991).

The formulations of the invention can be designed for to beshort-acting, fast-releasing, long-acting, and sustained-releasing.Thus, the pharmaceutical formulations can also be formulated forcontrolled release or for slow release.

The instant compositions can also comprise, for example, micelles orliposomes, or some other encapsulated form, or can be administered in anextended release form to provide a prolonged storage and/or deliveryeffect. Therefore, the pharmaceutical formulations can be compressedinto pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections or as implants such as stents. Suchimplants can employ known materials such as silicones and biodegradablepolymers.

The compositions may contain, for example, from about 0.1% by weight, toabout 90% or more by weight, of the active material, depending on themethod of administration. Where the compositions comprise dosage units,each unit can contain, for example, from about 0.1 to 500 mg or more ofthe active ingredient. The dosage as employed for adult human treatmentcan range, for example, from about 0.1 to 1000 mg per day, depending onthe route and frequency of administration.

Specific dosages can be adjusted depending on conditions of the JAKrelated condition, the age, body weight, general health conditions, sex,and diet of the subject, dose intervals, administration routes,excretion rate, and combinations of drugs. Any of the above dosage formscontaining effective amounts are well within the bounds of routineexperimentation and therefore, well within the scope of the instantinvention. Generally, the total daily dose can typically range fromabout 1 mg/kg/day to about 500 mg/kg/day in single or in divided doses.Typically, dosages for humans can range from about 5 mg to about 100 mgper day, in a single or multiple doses.

A therapeutically effective dose or amount can vary depending upon theroute of administration and dosage form. Some compositions of theinstant invention is a formulation that exhibits a high therapeuticindex. The therapeutic index is the dose ratio between toxic andtherapeutic effects which can be expressed as the ratio between LD₅₀ andED₅₀. The LD₅₀ is the dose lethal to 50% of the population and the ED₅₀is the dose therapeutically effective in 50% of the population. The LD₅₀and ED₅₀ can be determined by standard pharmaceutical procedures inanimal cell cultures or experimental models.

Pharmaceutical preparations of the JAK inhibitors, such as the compound(I), either from alone or in combination with one or more additionalagents which may include but are not limited to cyclosporin A,rapamycin, tacrolimus, sirolimus, everolimus, micophenolate (e.g.Cellcept(R), Myfortic(R), etc.), azathioprine, brequinar,deoxyspergualin, leflunomide, sphingosine-1-phosphate receptor agonist(e.g. fingolimod, KRP-203, etc.), LEA-29Y, anti-IL-2 receptor antibody(e.g. daclizumab, etc.), anti-CD3 antibody (e.g. OKT3, etc.), Anti-Tcell immunogloblin (e.g. AtGam, etc.), aspirin, CD28-B7 blockingmolecules (e.g. Belatacept, Abatacept, etc.), CD40-CD154 blockingmolecules (e.g. Anti-CD40 antibody, etc.), protein kinase C inhibitor(e.g. AEB-071, etc.), acetaminophen, ibuprofen, naproxen, piroxicam,methotrexate, an anti inflammatory steroid (e.g. prednisolone ordexamethasone) or those disclosed in PCT application no.PCT/IB2007/002468. These combinations can be administrated as part ofthe same or separate dosage forms, via the same or different routes ofadministration, and on the same or different administration schedulesaccording to standard pharmaceutical practice.

Also provided is an article of manufacture comprising a pharmaceuticalcomposition comprising a provided compound contained within a packagingmaterial and a label or package insert which indicates that saidpharmaceutical composition can be used for treating a JAK relatedcondition, as described herein.

Methods of Treatment

In one embodiment, the invention provides methods of treating orpreventing a condition associated with JAK in a subject, such as amammal, i.e., a human or non-human mammal, comprising administering aneffective amount of one or more compounds described herein to thesubject. The JAK associated condition can be related to JAK1, JAK2,JAK3, and/or Tyk2. Suitable non-human subjects that can be treatedinclude domestic or wild animals, companion animals, such as dogs, catsand the like; livestock, including horses, cows and other ruminants,pigs, poultry, rabbits and the like; primates, for example monkeys, suchas macaques including rhesus monkeys and cynomolgus (also known ascrab-eating or long-tailed) monkeys, marmosets, tamarins and the like,apes, including chimpanzees and orangutans; and rodents, such as rats,mice, gerbils, guinea pigs and the like. In one embodiment, the compoundis administered in a pharmaceutically acceptable form, optionally in apharmaceutically acceptable carrier.

JAK/STAT signaling has been implicated in the mediation of many abnormalimmune responses such as allergies, asthma, autoimmune diseases such astransplant (allograft) rejection, rheumatoid arthritis, amyotrophiclateral sclerosis and multiple sclerosis, as well as in solid andhematologic malignancies such as leukemia and lymphomas. For a review ofthe pharmaceutical intervention of the JAK/STAT pathway see Frank,(1999), Mol. Med. 5:432:456 and Seidel et al., (2000), Oncogene19:2645-2656.

JAK3 in particular has been implicated in a variety of biologicalprocesses. For example, the proliferation and survival of murine mastcells induced by IL-4 and IL-9 have been shown to be dependent on JAK3and gamma chain-signaling. Suzuki et al., (2000), Blood 96:2172-2180.JAK3 also plays a crucial role in IgE receptor-mediated mast celldegranulation responses (Malaviya et al., (1999), Biochem. Biophys. Res.Commun. 257:807-813), and inhibition of JAK3 kinase has been shown toprevent type I hypersensitivity reactions, including anaphylaxis(Malaviya et al., (1999), J. Biol. Chem. 274:27028-27038). JAK3inhibition has also been shown to result in immune suppression forallograft rejection (Kirken, (2001), Transpl. Proc. 33:3268-3270). JAK3kinases have also been implicated in the mechanism involved in early andlate stages of rheumatoid arthritis (Muller-Ladner et al., (2000), J.Immunal. 164:3894-3901); familial amyotrophic lateral sclerosis (Trieuet al., (2000), Biochem Biophys. Res. Commun. 267:22-25); leukemia(Sudbeck et al., (1999), Clin. Cancer Res. 5:1569-1582); mycosisfungoides, a form of T-cell lymphoma (Nielsen et al., (1997), Prac.Natl. Acad. Sci. USA 94:6764-6769); and abnormal cell growth (Yu et al.,(1997), J. Immunol. 159:5206-5210; Catlett-Falcone et al., (1999),Immunity 10:105-115).

The JAK kinases, including JAK3, are abundantly expressed in primaryleukemic cells from children with acute lymphoblastic leukemia, the mostcommon form of childhood cancer, and studies have correlated STATactivation in certain cells with signals regulating apoptosis (Demoulinet al., (1996), Mol. Cell. Biol. 16:4710-6; Jurlander et al., (1997),Blood 89:4146-52; Kaneko et al., (1997), Clin. Exp. Immun. 109:185-193;and Nakamura et al., (1996), J. Biol. Chem. 271: 19483-8). They are alsoknown to be important to lymphocyte differentiation, function andsurvival. JAK-3 in particular plays an essential role in the function oflymphocytes, macrophages, and mast cells. Given the importance of thisJAK kinase, compounds which modulate the JAK pathway, including thoseselective for JAK3, can be useful for treating conditions where thefunction of lymphocytes, macrophages, or mast cells is involved (Kudlaczet al., (2004) Am. J. Transplant 4:51-57; Changelian (2003) Science302:875-878).

Conditions in which targeting of the JAK pathway or modulation of theJAK kinases, particularly JAK3, are contemplated to be therapeuticallyuseful include, arthritis, asthma, autoimmune diseases, cancers ortumors, diabetes, certain eye diseases, disorders or conditions,inflammation, intestinal inflammations, allergies or conditions,neurodegenerative diseases, psoriasis, transplant rejection, and viralinfection. Conditions which can benefit for inhibition of JAK3 arediscussed in greater detail below.

Accordingly, the described compounds, pharmaceutically acceptable saltsand pharmaceutical compositions can be used to treat a variety ofconditions such as the following.

In some embodiments, the methods and compositions of the presentinvention encompass the treatment of the connective tissue and jointdisorders such as arthritis, rheumatoid arthritis, ankylosingspondylitis, fibromyalgia, spondyloarthopathies, gouty arthritis, lumbarspondylarthrosis, carpal tunnel syndrome, psoriatic arthritis,sclerodoma, canine hip dysplasia, systemic lupus erythematosus, juvenilearthritis, osteoarthritis, tendonitis and bursitis.

In other embodiments, the methods and compositions of the presentinvention encompass the treatment of neuroinflammation andneurodegenerative disorders such as Alzheimer's disease, multiplesclerosis (MS), Parkinson's disease, motor neuron disease, amyotrophiclateral sclerosis, Huntington's disease, cerebral ischemia,neurodegenerative disease caused by traumatic injury, the neurologicalcomplications of AIDS, spinal cord injury, and some peripheralneuropathies and neurodegenerative disorders.

In other embodiments, the methods and compositions of the presentinvention encompass the treatment of autoimmune diseases or disorders,including those designated as single organ or single cell-typeautoimmune disorders, for example Hashimoto's thyroiditis, autoimmunehemolytic anemia, autoimmune atrophic gastritis of pernicious anemia,autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture'sdisease, autoimmune thrombocytopenia, sympathetic ophthalmia, myastheniagravis, Graves' disease, primary biliary cirrhosis, chronic aggressivehepatitis, ulcerative colitis and membranous glomerulopathy, Sjogren'ssyndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemicsclerosis, polyarteritis nodosa, multiple sclerosis and bullouspemphigoid, and additional autoimmune diseases, which can be O-cell(humoral) based or T-cell based, including Cogan's syndrome, Wegener'sgranulomatosis, autoimmune alopecia, and thyroiditis.

In other embodiments, the methods and compositions of the presentinvention encompass the treatment of diabetes, including Type Idiabetes, juvenile onset diabetes and complications from diabetes.

In other embodiments, the methods and compositions of the presentinvention encompass the treatment of cancers or tumors, includingalimentary/gastrointestinal tract cancer, colon cancer, liver cancer,skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma,leukemia, including acute myelogenous leukemia and chronic myelogenousleukemia, T-cell prolymphocytic leukemia, kidney cancer, lung cancer,muscle cancer, bone cancer, bladder cancer, brain cancer, metastaticmelanoma, Kaposi's sarcoma, myelomas including multiple myeloma,myeloproliferative disorders, proliferative diabetic retinopathy, andangiogenic-associated disorders including solid tumors

In other embodiments, the methods and compositions of the presentinvention encompass the treatment of respiratory disorders such asasthma, bronchitis, chronic obstructive pulmonary disease (COPD), airwayhyper-responsiveness, bronchial asthma, allergic asthma, intrinsicasthma, extrinsic asthma, dust asthma, cystic fibrosis, pulmonary edema,pulmonary embolism, pneumonia, pulmonary sarcoisosis, silicosis,pulmonary fibrosis, respiratory failure, acute respiratory distresssyndrome and emphysema.

In other embodiments, the methods and compositions of the presentinvention encompass the treatment of viral infections such as EpsteinBarr Virus, Hepatitis B, Hepatitis C, HIV, HTLV1, Varicella-ZosterVirus, and Human Papilloma Virus.

In other embodiments, the methods and compositions of the presentinvention encompass the treatment of the dermatological disorders suchas acne, psoriasis, eczema, burns, poison ivy, poison oak, dermatitis,atopic dermatitis, pruritus and scleroderma.

In other embodiments, the methods and compositions of the presentinvention encompass the treatment of the allergic reactions, allergicdermatitis, recurrent airway obstruction, heaves, inflammatory airwaydisease and otitis.

In other embodiments, the methods and compositions of the presentinvention encompass the treatment of the surgical disorders such as painand swelling following surgery, infection following surgery andinflammation following surgery.

In other embodiments, the methods and compositions of the presentinvention encompass the treatment of transplant rejection, includingpancreas islet transplant rejection, bone marrow transplant rejection,graft-versus-host disease, organ and cell transplant rejection such asbone marrow, cartilage, cornea, heart, intervertebral disc, islet,kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin,small intestine, or trachea, chronic and acute allograft transplantrejection and xeno transplantion.

In other embodiments, the methods and compositions of the presentinvention encompass the treatment of the gastrointestinal disorders suchas inflammatory bowel disease, irritable bowel syndrome, Crohn'sdisease, gastritis, irritable bowel syndrome, diarrhea, constipation,dysentery, ulcerative colitis, gastric esophageal reflux, gastriculcers, gastric varices, ulcers, heartburn, coeliac diseases, proctitis,eosinophilic gastroenteritis, and mastocytosis.

In other embodiments, the methods and compositions of the presentinvention encompass the treatment of the ophthalmic disorders such asretinopathies, uveitis, ocular photophobia, acute injury to the eyetissue, conjunctivitis, age-related macular degeneration diabeticretinopathy, detached retina, glaucoma, vitelliform macular dystrophytype 2, gyrate atrophy of the choroid and retina, conjunctivitis,corneal infection, fuchs' dystrophy, iridocorneal endothelial syndrome,keratoconus, lattice dystrophy, map-dot-fingerprint dystrophy, ocularherpes, pterygium, myopia, hyperopia, cataracts, keratoconjunctivitis,vernal conjunctivitis, keratitis, herpetic keratitis, conical keratitis,corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren'sulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome,keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis,sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis,allergic conjunctivitis, and ocular neovascularization.

In other embodiments, the methods and compositions of the presentinvention encompass the treatment of pain, including but not limited tochronic pain, acute pain, joint pain, nociceptive pain, neuropathicpain, allodynia, hyperalgesia, burn pain, menstrual cramps, kidneystones, headache, migraine headache, sinus headaches, tension headaches,dental pain, myasthenia gravis, multiple sclerosis, sarcoidosis,Behcet's syndrome, myositis, polymyositis, gingivitis, hypersensitivity,swelling occurring after injury, closed head injury, endometriosis,vasculitis, sepsis, glutamate neurotoxicity or hypoxia;ischemic/reperfusion injury in stroke, myocardial ischemica, renalischemia, heart attacks, stroke, cardiac hypertrophy, coronary arterydisease, atherosclerosis and arteriosclerosis, organ hypoxia, andplatelet aggregation, stroke, and the like.

Additional examples of the diseases and disorders associated with JAKinhibition and that can be treated include those disclosed in WO2007/077949, U.S. patent publication nos. US 2007/0259904, US2007/0207995, US 2007/0203162, and US 2006/0293311.

The compounds described herein can also be used prophylactically for theprevention of organ transplant rejection. For example, the compounds andpharmaceutical formulations of the present invention can be administeredbefore, during, and/or after a surgical procedure, such as an organtransplant surgery.

Another embodiment provides a method of inhibiting a JAK enzyme,including JAK-1, JAK-2, JAK-3 and/or Tyk-2, that includes contacting theJAK enzyme with either a non-therapeutic amount or a therapeuticallyeffective amount of one or more of the present compounds. Such methodscan occur in vivo or in vitro. In vitro contact can involve a screeningassay to determine the efficacy of the one or more compounds against aselected enzyme at various amounts or concentrations. In vivo contactwith a therapeutically effective amount of the one or more compounds caninvolve treatment of a described condition or prophylaxis of organtransplant rejection in the animal in which the contact occurs. Theeffect of the one or more compounds on the JAK enzyme and/or host animalcan also be determined or measured. Methods for determining JAK activityinclude those described in the Examples as well as those disclosed in WO99/65908, WO 99/65909, WO 01/42246, WO 02/00661, WO 02/096909, WO2004/046112 or WO 2007/012953.

Chemical Synthesis

Representative procedures for the preparation of compounds of theinvention are outlined below in the Schemes. The starting materials canbe purchased or prepared using methods known to those skilled in theart. Similarly, the preparation of the various intermediates can beachieved using methods known in the art. The starting materials may bevaried and additional steps employed to produce compounds encompassed bythe invention, as demonstrated by the examples below. In addition,different solvents and reagents can typically be used to achieve theabove transformations. Furthermore, in certain situations, it may beadvantageous to alter the order in which the reactions are performed.Protection of reactive groups may also be necessary to achieve the abovetransformations. In general, the need for protecting groups, as well asthe conditions necessary to attach and remove such groups, will beapparent to those skilled in the art of organic synthesis. When aprotecting group is employed, deprotection will generally be required.Suitable protecting groups and methodology for protection anddeprotection such as those described in Protecting Groups in OrganicSynthesis by Greene and Wuts are known and appreciated in the art.

The compounds described herein can be synthesized as set forth in theexamples of the present application.

General Synthetic Procedure 1

The compounds described herein can also be synthesized according to thefollowing general Scheme I:

In some synthetic methods, functional groups may need to be protectedand deprotected during, synthesis of a compound of the invention. In thepresent application protecting groups are indicated by the letters. Pgalone or with a numerical designation, such as Pg or Pg1. Those skilledin the art recognize that protection and deprotection of compounds canbe achieved by conventional methods, for example as described in“Protective Groups in Organic Synthesis” by T W Greene and P G M Wuts,John Wiley & Sons Inc (1999), and references therein.

In Scheme I, 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (a) can be obtained Idcommercially (GL Synthesis, Inc., Worchester, Mass.).4-[(Methylamino)-cyclohexyl]-methanol (b) can be obtained from thecorresponding carboxylic acid,4-[(tert-butoxy-carbonyl)amino]cyclohexanecarboxylic acid, by treatmentwith a reducing agent, such as lithium aluminium hydride, which canoccur in an aprotic, anhydrous solvent, such as tetrahydrofuran.Conversion of (a) to (b) can occur at a range of temperatures, typicallybetween about 0 to 60° C. and completion of the reaction can take up toseveral hours.

As shown in Scheme I, a compound of structure (c) can be synthesized bythe reaction of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (a) with4-[(methylamino)-cyclohexyl]methanol (b) in a suitable solvent, such asa polar, aprotic solvent, for example N,N-dimethylformamide, aqueousdioxane and/or dimethylsulfoxide, in the presence of a suitable base,such as triethylamine and/or potassium carbonate. This reaction canoccur at elevated temperatures up to about 90° C. and the reaction canoccur for up to a few hours or longer.

A compound of structure (d) can be synthesized from a compound ofstructure (c) as shown above. For example, a compound of structure (d)can be synthesized by using a brominating reagent, such as thionylbromide or phosphorous tribromide, in a polar, aprotic solvent, such asmethylene chloride, to afford an unprotected cyclohexylmethylbromide,and which can give the protected compound of structure (d) by additionof a suitable protecting reagent, such as tosyl chloride.

A compound of structure (e) can be prepared by using protectionprocesses from a compound of structure (c). For example, when Pg and Pg1are both tosyl, (e) can be prepared in a one step reaction upontreatment of the unprotected compound of structure (c) with tosylchloride in the presence of a polar, aprotic solvent, such as methylenechloride, a catalyst, such as DMAP, and a weak base, such astriethylamine.

A compound of structure (f) can be synthesized from a compound ofstructure (e) by S-alkylation using a suitable nucleophile. Thuscompounds of structure (e), wherein the protecting group (Pg1)) is asuitable hydroxyl protecting group such as tosyl or mesyl, can bereacted with potassium thioacetate in a polar solvent, such asdimethylsulfoxide or N-methylpyrrolidine, to give compounds of structure(f). This reaction can occur at elevated temperatures up to 75° C. andcan take place for up to 2 hours or longer.

A compound of structure (g) can be synthesized by an oxidation procedurefrom the compound of formula (f). The oxidation step is not critical tothe present scheme, and many oxidizing conditions are known to thoseskilled in the art, for example those described in “Handbook of Reagentsfor Organic Synthesis—Oxidising and Reducing Agents” edited by S. D.Burke and R. L. Danheiser. In some embodiments, a compound of structure(f), optionally wetted with water, can be treated with formic acidfollowed by slow addition of hydrogen peroxide. Such a reaction canoccur with stirring at room temperature, for a time up to about 15 hoursor more, to give a compound of structure (g). Alternatively, Oxone®(DuPont) may be employed in a polar solvent such as acetic acid. In oneembodiment, the reaction is performed in the presence of potassiumacetate and the potassium salt of the compound of formula (g) isproduced.

A compound of structure (g) can be synthesized directly from a compoundof structure (e) upon treatment with a suitable sulfur nucleophile, suchas sodium sulfite, in a polar solvent. Alternatively, a compound ofstructure (g) can be synthesized from a compound of structure (d) uponnucleophilic substitution with sodium sulfite.

Treatment of sulphonic acids of formula (g) with a chlorinating agent,such as thionyl chloride, in a polar, aprotic solvent, such as methylenechloride, with a polar cosolvent, such as N,N-dimethylformamide, canprovide the appropriate chlorinated compounds. This reaction can occurunder reflux conditions. The chlorinated compound can then react in anaprotic, anhydrous solvent, such as tetrahydrofuran, with a suitableamine, which can be in neat, gaseous form, or dissolved in an aprotic,anhydrous solvent such as tetrahydrofuran, to produce a compound ofstructure (h). In some embodiments, this reaction can occur at roomtemperature. Optionally an anhydrous, weak base, such as triethylamine,may be used to mop up hydrochloric acid generated in the reaction.

Compounds of formula Ia of the present invention can be prepared fromcompounds of formula (h), wherein Pg is a suitable protecting group, bydeprotection procedures known to those skilled in the art. For example,when the protecting group (Pg) is tosyl, suitable deprotectionconditions involve reaction with a base, such as lithium hydroxide orpotassium hydroxide in a protic solvent such as methanol or isopropanoland optionally miscible cosolvents such as tetrahydrofuran and water.This deprotection reaction can occur at about room temperature forseveral hours or more and thereby produce the deprotected amine offormula Ia.

General Synthetic Procedure 2

The compounds described herein were synthesized according to thefollowing general Scheme 2

In the Examples, Ts refers to a tosyl group, haying the followingstructure where

indicates the point of attachment:

Step 1: To a 250 ml round bottom flask charged with((1r,4r)-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonicacid (4.2 g, 8.75 mmol), dichloromethane (80 mL) andN,N′-dimethylformamide (300 μL), thionyl chloride (10 mL) was addedslowly over 10 minutes at 22-28° C. (the reaction was exothermic and gasevolved during addition). The reaction mixture was heated to reflux for3 hours. The reaction was cooled to room temperature and stirredovernight under N₂. Most of solvents were evaporated at reduced pressureand then at high vacuum for at least 2 hours to give a dry brown solidwhich was used immediately for the next step without any purification.

Step 2: 2 mL (125 μmol) of freshly prepared sulfonyl chloride from Step1 (0.0625M) in anhydrous N,N′-dimethylformamide was added to vialcharged with 200 μmol of the appropriate amine, R₁R₂NH, followed by 100μL of triethylamine. After the reaction mixture was shaken at roomtemperature for 16 hours, the solvent was evaporated under reducedpressure. A solution of 2 mL of 5% Na₂CO₃ and 2 mL of ethyl acetate wereadded to the vial. The mixture was vortexed and centrifuged. The organicphase was collected and concentrated to dryness under reduced pressure.

Step 3: Samples were re-dissolved in 1 mL of MeOH/THF/H2O (2/2/1,v/v/v). 0.1 mL of 2N lithium hydroxide (200 μmol) was added and thereaction mixtures were stirred at room temperature overnight. Solventwas removed and the samples were diluted with 1.5 mL ofdimethylsulfoxide, purified by HPLC.

Example 1

N-cyclopropyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamideStep 1: Synthesis ofN-cyclopropyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide

Trans-4-(Methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methane-sulfonicacid (0.5 g, 1.04 mmol) was suspended in a solution of dichloromethane(4 mL) and N,N′-dimethylformamide (50 μL). The system was flushed withnitrogen and thionyl chloride (0.38 mL, 5.22 mmol) was added dropwise.The reaction mixture was heated at 40-45° C. for 2 hours, concentratedin vacuo and the residue was dissolved in chloroform (5 mL).Triethylamine (0.3 mL) was added followed by a solution of(3R)-3-pyrrolidinol (60 mg, 1.0 mmol) in chloroform (5 mL): The reactionmixture was stirred under nitrogen at room temperature overnight. Thereaction mixture was diluted with ethyl acetate and washed withsaturated aqueous NaHCO₃. The organic layer was washed with brine andconcentrated in vacuo. The residue was dissolved in a mixture oftetrahydrofuran (3 mL), methanol (3 mL) and water (1 mL). Lithiumhydroxide (50 mg, 2.08 mmol) was added and the reaction mixture wasstirred at room temperature overnight. The reaction mixture wasevaporated and water was added. The resulting precipitate was filteredand washed with water. The product was isolated as a white solid (201mg, 53%). LCMS m/z 364.2 (M+H calcd for C₁₇H₂₅N₅O₂S is 363.4). LCMS(C-18 column, gradient elution 10 minute chromatograph, 95:5 to 5:95water/acetonitrile, retention time 3.38 min).

The compounds in Table 1 were synthesized according to General SyntheticProcedure 1

TABLE 1 Low Resolution LCMS Example Structure Compound Name (M + H) 2

4-(2-{[({trans-4-[methyl(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methyl) sulfonyl]amino}ethyl)benzene- sulfonamide507.1 3

N-[2-(4-hydroxyphenyl)-ethyl]- 1-{trans-4-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide 4444

N-[2-(2,4-dimethylphenyl)- ethyl]-1-{trans-4-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide 4565

N-[2-(2-methoxyphenyl)- ethyl]-1-{trans-4-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide 4586

N-(2,2-difluoro-2-phenyl- ethyl)-1-{trans-4-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide 4647

N-[2-(4-methylphenyl)-ethyl]- 1-{trans-4-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide 4428

N-[2-fluoro-2-(4-fluoro- phenyl)propyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)amino]- cyclohexyl}-methanesulfonamide 478 9

N-[2-fluoro-2-(3-fluoro- phenyl)propyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)amino]- cyclohexyl}-methanesulfonamide 478 10

N-[2-(3-methoxyphenyl)- ethyl]-1-{trans-4-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide458.2 11

N-[2-fluoro-2-(4-fluoro- phenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)amino]- cyclohexyl}-methanesulfonamide 464 12

1-{trans-4-[methyl(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-{2-[4- (trifluoromethyl)-phenyl]ethyl}-methanesulfonamide 496 13

N-{2-[2-fluoro-4-(trifluoro- methyl)phenyl]ethyl}-1-{trans-4-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4- yl)amino]cyclohexyl}-methanesulfonamide 514

Example 14

N-[2-(2-fluorophenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide

Step 1: To a 250 ml round bottom flask charged with ((1r,4r)-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonicacid (4.2 g, 8.75 mmol), dichloromethane (80 mL) andN,N′-dimethylformamide (300 μL), thionyl chloride (10 mL) was addedslowly over 10 minutes at 22-28° C. (the reaction was exothermic and gasevolved during addition). The reaction mixture was heated to reflux for3 hours. The reaction was cooled to room temperature and stirredovernight under N₂. Most of solvents were evaporated at reduced pressureand then at high vacuum for at least 2 hours to give a dry brown solidwhich was used immediately for the next step without any purification.

Step 2: 2 mL (125 μmol) of freshly prepared sulfonyl chloride from Step1 (0.0625M) in anhydrous N,N′-dimethylformamide was added to vialcharged with 200 μmol of (2-fluorophenyl)ethyl amine, followed by 100 μLof triethylamine. After the reaction mixture was shaken at roomtemperature for 16 hours, the solvent was evaporated under reducedpressure. A solution of 2 mL of 5% Na₂CO₃ and 2 mL of ethyl acetate wasadded to the vial. The mixture was vortexed and centrifuged. The organicphase was collected and concentrated to dryness under reduced pressure.The sample were re-dissolved in 1 mL of MeOH/THF/H2O (2/2/1, v/v/v). 0.1mL of 2N lithium hydroxide (200 μmol) was added and the reaction mixturewas stirred at room temperature overnight. Solvent was removed and thesample was diluted with 1.5 mL of dimethylsulfoxide and purified byHPLC. LCMS m/z 446.3 (M+H calcd for C₂₂H₂₈FN₅O₂S is 446.5).

The compounds in Table 2 were synthesized according to General SyntheticProcedure 2.

TABLE 2 Low Resolution LCMS Example Structure Compound Name (M + H) 15

1-{trans-4-[methyl(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)amino]-cyclohexyl}-N-(2-phenylethyl)- methanesulfonamide 428.1 16

N-benzyl-1-{trans-4-[methyl- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclohexyl}- methanesulfonamide 414.6 17

N-(2-hydroxyethyl)-N-methyl- 1-{trans-4-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide382.3 18

N-(4-methoxybenzyl)-1-{trans- 4-[methyl(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)amino]-cyclo- hexyl}methanesulfonamide 444.5 19

1-{trans-4-[methyl(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N- (pyridin-3-ylmethyl)- methanesulfonamide 415.520

N-[4-(cyanomethyl)phenyl]-1- {trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}methane- sulfonamide439.1 21

N-(4-cyanophenyl)-1-{trans-4- [methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclohexyl}- methanesulfonamide 425.4 22

1-{trans-4-[methyl(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-1H- pyrazol-5-yl- methanesulfonamide 390.5 23

N-(5-methyl-1H-pyrazol-3-yl)- 1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide404.5 24

N-1H-indol-5-yl-1-{trans-4- [methyl(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)amino]- cyclohexyl}- methanesulfonamide 439.4 25

N-(6-chloropyridin-3-yl)-1- {trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- amino]cyclohexyl}- methanesulfonamide435.1 26

N-1H-indazol-5-yl-1-{trans-4- [methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]- cyclohexyl}- methanesulfonamide 440.1 27

N-(3,4-dihydro-2H-1,5- benzodioxepin-7-yl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)amino]-cyclo-hexyl}methanesulfonamide 472.4 28

N-(6-methoxypyridin-3-yl)-1- {trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}methane- sulfonamide431.5 29

N-[(6-aminopyridin-2- yl)methyl]-N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4- yl)amino]cyclohexyl}-methanesulfonamide 444.5 30

N-(6-methylpyridin-3-yl)-1- {trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide415.4 31

N-[2-(4-chlorophenyl)ethyl]-1- {trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide462.35 32

1-{trans-4-[methyl(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N- [(1S,2R)-2- phenylcyclopropyl]-methanesulfonamide 440.35 33

N-[2-(3-fluorophenyl)ethyl]-1- {trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide446.35 34

N-[(2-methyl-1H-indol-5- yl)methyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)amino]- cyclohexyl}-methanesulfonamide 467.15 35

N-methyl-1-{trans-4- [methyl(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)amino]-cyclohexyl}-N-(pyridin-3- ylmethyl)- methanesulfonamide 429.35 36

N-[2-(3-chlorophenyl)ethyl]-1- {trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide462.35 37

N-[trans-4-(1-hydroxy-1- methylethyl)cyclohexyl]-1- {trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide464.25 38

N-[2-(2-fluoro-4- isopropylphenyl)ethyl]-1- {trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide488.25 39

N-[2-(3,4-difluorophenyl)-2- hydroxyethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino]- cyclohexyl}-methanesulfonamide 480.25 40

N-[3-(2-methoxyphenyl)- propyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]-pyrimidin-4- yl)amino]-cyclohexyl}- methanesulfonamide472.35 41

tert-butyl (3-{[({trans-4- [methyl(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)amino]- cyclohexyl}methyl)sulfonyl]amino}cyclobutyl)-carbamate 493.35 42

N-[2-(3,4-dichlorophenyl)- ethyl]-1-{trans-4-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide496.55 43

N-methyl-1-{trans-4- [methyl(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)amino]-cyclohexyl}-N-(pyrazin-2- ylmethyl)- methanesulfonamide 430.45 44

N-(1-benzylcyclobutyl)-1- {trans-4-[methyl(7H-pyrrolo-[2,3-d]pyrimidin-4-yl)amino]- cyclohexyl}methane- sulfonamide 468.65 45

N-[(5-methylpyrazin-2- yl)methyl]-1-{trans-4- [methyl(7H-pyrrolo[2,3-d]-pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide 430.35 46

N-[(1R,2R)-2-(4-fluoro- phenyl)cyclopentyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4- yl)amino]cyclohexyl}-methanesulfonamide 486.55 47

1-{trans-4-[methyl(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-[(2R)- tetrahydrofuran-2-ylmethyl]-methanesulfonamide 408.35 48

1-{trans-4-[methyl(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-(3,4,4- trifluorobut-3-en-1-yl)methanesulfonamide 432.35 49

N-[(2S)-2-hydroxypropyl]-1- {trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclohexyl}- methanesulfonamide382.15 50

N-[2-(6-methylpyridin-2- yl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)amino]- cyclohexyl}-methanesulfonamide 443.45 51

N-[(4,6-dimethylpyrimidin-2- yl)methyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]- pyrimidin-4- yl)amino]cyclohexyl}-methanesulfonamide 444.45 52

N-[(1,3-dimethyl-1H-pyrazol- 4-yl)methyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4- yl)amino]cyclohexyl}-methanesulfonamide 432.35 53

1-{cis-4-[methyl(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-(2- phenylethyl)- methanesulfonamide 428.0 54

N-benzyl-1-{cis-4-[methyl(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}- methanesulfonamide 414.5 55

N-(cyclopropylmethyl)-1-{cis- 4-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclohexyl}- methanesulfonamide 378.1 56

N-(4-methoxybenzyl)-1-{cis-4- [methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclohexyl}- methanesulfonamide 444.5

Example 57

N,N-dimethyl((1r,4r)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-cyclohexyl)-methanesulfonamide

Step 1: To a chloroform (2 ml) solution of((1r,4r)-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)amino)cyclohexyl)methanesulfonylchloride (100 mg, 0.20 mmols) was added a solution of 2.0M dimethylaminein THF (1.0 ml,). The reaction was stirred at room temperature for onehour. The volatiles were removed by rotary evaporation at low pressureto afford a viscous oil. The oil was dissolved in a small volume ofmethylene chloride and applied to a 10 g cartridge of silica gel. Thecartridge was eluted with an acetone/heptane gradient which providedpure product, N,N-dimethyl((1r,4r)-4-(methyl(7-tosyl-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide, as awhite solid (76 mg, 75%).

Step 2: To a methanolic (5 ml) mixture ofN,N-dimethyl((1r,4r)-4-(methyl(7-tosyl-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide wasadded cesium carbonate (97 mg, 0.3 mmols). The reaction was stirred at50 degrees Celcius for four hours. The product was precipitated in pureform through the addition of water (10 ml) to the reaction mixture. Theproduct.N,N-dimethyl((1r,4r)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamidewas captured by suction filtration and dried under vacuum (36 mg, 66%)¹H NMR (400 MHz, CHLOROFORM-d) d ppm 1.35-1.47 (m, 2H) 1.68-1.79 (m, 2H)1.88-1.97 (m, 2H) 2.02-2.10 (m, 1H) 2.17-2.25 (m, 2H) 2.83 (d, J=6.32Hz, 2H) 2.91 (s, 6H) 3.26 (s, 3H) 4.82 (br. s., 1H) 6.57 (d, J=3.28 Hz,1H) 7.05 (d, J=2.78 Hz, 1H) 8.32 (s, 1H) 9.98 (br. s., 1H); m/z (Cl) 352([M+H]⁺.

Biological Evaluation JAK Enzymatic Assay Materials

Recombinant JAK1 (Catalog Number PV4775), JAK2 (Catalog Number PV4210)and JAK3 (Catalog Number PV3855) were purchased from (InvitrogenCorporation, Madison, Wis.). Tyk2 (His-Tyk2 (888-1182, C936S, C1142S))used in this study was expressed and purified at Pfizer Laboratories.Adenosine 5′-triphosphate (ATP) was obtained from (Sigma ChemicalCompany, St. Louis, Mo.). The JAKtide peptide (peptide sequence,FITC-KGGEEEEYFELVKK) used for the JAK2 and JAK3 assays and the IRS-1peptide (peptide sequence, 5-FAM-KKSRGDYMTMQIG) used for the JAK1 andTyk2 assays were purchased from (American Peptide Company, Sunnyvale,Calif.). Coating Reagent 3 was purchased from (Caliper Life Sciences,Hopkinton, Mass.).

Methods

A peptide mobility shift assay was used to quantify the phosphorylationof the JAKtide (JAK2 and JAK3) or the IRS-1 peptide (JAM and Tyk2).Reactions were carried out in a 384-well plate (Matrical MP-101) in a 10μL total volume. Reaction mixtures contained 20 mM HEPES, pH 7.4, 10 mMmagnesium chloride, 0.01% bovine serum albumin (BSA), 0.0005% Tween-20,ATP (4 μM for JAK2 and JAK3, 40 μM for JAK1 and 7 μM for Tyk2)), 2% DMSOand 1 μM peptide substrate (JAKtide for JAK2 and JAK3 and IRS-1 peptidefor JAK1 and Tyk2). Compounds were diluted serially in 100% dimethylsulfoxide and tested in an 11 point dose response in duplicate orquadruplicate (200 nl of compound/DMSO was added per 10 μL reaction).The reactions were initiated by the addition of enzyme to the finalconcentration of 2 nM JAK2, 1 nM JAK3, 12 nM Tyk2 or 20 nM JAK1. Theassay was run for 240 minutes for JAK1, 150 minutes for JAK2, 90 minutesfor JAK3 and 70 minutes for Tyk2. The assays were stopped at thespecified times with 20 uL of 140 mM HEPES, 22.5 mM EDTA and 0.15%Coating Reagent 3. The plates were placed on a LabChip 3000 (LC3000)instrument from (Caliper Life Sciences) to measure the formation ofphosphorylated peptide. Data was analyzed using Hits Well AnalyzerSoftware from (Caliper Life Sciences) to obtain the amount of productformed.

Data was then imported into an internal application where each datapoint is expressed as % inhibition based on uninhibited and no enzymecontrols. Dose-response data is then fit using a 4 parameter logisticequation (Equation 1) to determine an IC₅₀.

Equation 1:

$y = {\frac{\max - \min}{1 + ( \frac{x}{{IC}_{50}} )^{s}} + \min}$

Where max is the fitted uninhibited value, min is the fitted completeinhibition value, and s is the slope factor.

Using this protocol, the following results were generated:

Example JAK3:IC50 (μM) JAK2:IC50 (μM) JAK1:IC50 (μM) 1 0.224 0.0454 0.012 0.166 0.0149 0.00182 3 0.257 0.0286 0.00225 4 0.139 0.00917 0.00301 50.188 0.017 0.00378 6 0.101 0.0118 0.00422 7 0.137 0.0113 0.00444 80.403 0.0323 0.00605 9 0.531 0.0397 0.0105 10 0.301 0.0341 0.011 110.424 0.0619 0.0135 12 0.511 0.0555 0.0165 13 0.563 0.0553 0.0174 140.148 0.0205 0.00465 15 0.0878 0.012 0.00287 16 0.182 0.0294 0.0135 170.332 0.0442 0.0163 18 0.175 0.0275 0.0213 19 0.376 0.0579 0.0093 200.0961 0.0381 0.00958 21 0.14 0.0524 0.0103 22 0.241 0.0324 0.0152 230.342 0.0305 0.0186 24 0.0558 0.00455 0.00165 25 0.228 0.0574 0.0186 260.175 0.0394 0.019 27 0.0543 0.00747 0.00219 28 0.121 0.0222 0.00872 290.514 0.051 0.0167 30 0.221 0.0476 0.0165 31 0.154 0.019 0.00367 320.144 0.0236 0.00434 33 0.192 0.0242 0.00495 34 0.224 0.0247 0.00676 350.622 0.0761 0.00685 36 0.294 0.0414 0.0077 37 0.212 0.0333 0.00873 380.145 0.0554 0.00913 39 0.24 0.0306 0.00979 40 0.208 0.0298 0.0107 410.292 0.123 0.0116 42 0.427 0.0557 0.0145 43 0.517 0.0532 0.0149 440.641 0.112 0.0151 45 0.49 0.0497 0.0153 46 0.355 0.0184 0.0156 47 1.060.174 0.0161 48 0.267 0.066 0.0196 49 0.526 0.0642 0.0214 50 0.6330.0806 0.0216 51 0.237 0.0202 0.0233 52 0.762 0.107 0.024 53 0.1190.0347 0.0115 54 0.162 0.0542 0.0193 55 0.201 0.0341 0.0114 56 0.1140.0366 0.0107 57 0.174 0.0275 0.00733

Mouse Collagen Induced Arthritis Model

Male DBA/1 mice, 8-10 weeks of age (18-22 g), are obtained from HarlanLaboratories (Indianapolis, Ind.) and provided food and water adlibitum. Mice are immunized subcutaneously with 50 μg of chicken type IIcollagen (Dr. Marie Griffiths, University of Utah) emulsified incomplete Freund's adjuvant (Sigma, St. Louis, Mo.), and boosted 21 dayslater with 50 μg of the same antigen in incomplete Freund's adjuvant(Sigma). The compound is resuspended in 0.5% methylcellulose/0.025%Tween-20 (Sigma) containing 50 mM citric acid monohydrate, pH 3 (FisherScientific; Pittsburgh, Pa.). Mice are administered vehicle or varyingdoses of the compound by oral gavage, and disease is monitored dailybeginning on day 35 post-immunization. Severity is scored on a scale of0-3 in each paw (maximum score of 12/mouse), where 0=no symptoms,1=redness or swelling of digits of the paw, 2=gross swelling ordeformity of the whole paw, 3=ankylosis of the joint, and is expressedas the average severity score for each treatment group. Area under thecurve (AUC) from a time course of disease severity is calculated foreach dose of compound and percent of control activity is used as ameasure of efficacy.

As used herein, reference to “a” or “an” means “one or more.”Throughout, the plural and singular should be treated asinterchangeable, other than the indication of number.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof as well as the individual valuesmaking up the range, particularly integer values. Any listed range canbe easily recognized as sufficiently describing and enabling the samerange being broken down into at least equal halves, thirds, quarters,fifths, tenths, etc. As a non-limiting example, each range discussedherein can be readily broken down into a lower third, middle third andupper third, etc. For example, the range C₁-C₆, includes the subrangesC₂-C₆, C₃-C₆, C₃-C₅, C₄-C₆, etc., as well as C₁ (methyl), C₂ (ethyl), C₃(propyl), C₄ (butyl), C₅ (pentyl) and C₆ (hexyl) individually. As willalso be understood by one skilled in the art, all language such as “upto,” “at least,” “greater than,” “less than,” “more than,” “or more” andthe like include the number recited and refer to ranges which can besubsequently broken down into subranges as discussed above. In the samemanner, all ratios disclosed herein also include all subratios fallingwithin the broader ratio.

One skilled in the art will also readily recognize that where membersare grouped together in a common manner, such as, in a Markush group,the present invention encompasses not only the entire group listed as awhole, but each member of the group individually and all possiblesubgroups of the main group. Additionally, for all purposes, the presentinvention encompasses not only the main group, but also the main groupabsent one or more of the group members. The present invention alsoenvisages the explicit exclusion of one or more of any of the groupmembers in the claimed invention.

As will be understood by the skilled artisan, all numbers, includingthose expressing quantities of ingredients, properties such as molecularweight, reaction conditions, and so forth, are approximations andunderstood as being modified in all instances by the term “about.” Thesevalues can vary depending upon the desired properties sought to beobtained by those skilled in the art utilizing the present teachings ofthe present invention. It is also understood that such values inherentlycontain variability necessarily resulting from the standard deviationsfound in their respective testing measurements.

The above detailed description of embodiments is intended only toacquaint others skilled in the art with the invention, its principles,and its practical application so that others skilled in the art mayadapt and apply the invention in its numerous forms, as they may be bestsuited to the requirements of a particular use. This invention,therefore, is not limited to the above embodiments, and may be variouslymodified.

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein: R¹ is selectedfrom the group consisting of hydrogen and (C₁-C₆)alkyl; and when R¹ ishydrogen, then R² is selected from the group consisting of (C₆-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₅-C₆)alkyl,(C₁-C₆)alkenyl, halo(C₁-C₆)alkenyl, phenyl, phenyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, heterocyclyl, and heterocyclyl(C₁-C₀)alkyl; when R¹is (C₁-C₆)alkyl, then R² is selected from the group consisting of(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkenyl, phenyl, phenyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, heterocyclyl, and heterocyclyl(C₁-C₆)alkyl; wherein(C₃-C₆)cycloalkyl, wherever it occurs, is optionally substituted withone or more substituents selected from the group consisting ofhydroxy(C₁-C₆)alkyl, phenyl, phenyl(C₁-C₆)alkyl, and(C₁-C₆)alkoxycarbonylamino; and wherein when R¹ is hydrogen and R² iscyclobutyl, then the cyclobutyl is substituted with one or moresubstituents selected from the group consisting of hydroxy(C₁-C₆)alkyl,phenyl, halophenyl, phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino;wherein phenyl, wherever it occurs, is optionally substituted with oneor more substituents independently selected from the group consisting ofcyano, halo, hydroxy, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl,(C₁-C₆)alkoxy, aminosulfonyl, and (C₁-C₆)alkylaminosulfonyl; whereinheterocyclyl, wherever it occurs; is optionally substituted with one ormore substituents independently selected from the group consisting ofhalo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, and (C₁-C₆)alkylamino; andwherein the (C₁-C₆)alkyl in phenyl(C₁-C₆)alkyl andheterocyclyl(C₁-C₆)alkyl is optionally substituted with one moresubstituents independently selected from the group consisting of haloand hydroxy; and R³ selected from the group consisting of hydrogen and(C₁-C₆)alkyl.
 2. The compound of claim 1, wherein R¹ is selected fromthe group consisting of hydrogen and (C₁-C₆)alkyl; and when R¹ ishydrogen, then R² is selected from the group consisting of (C₅-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₅-C₆)alkyl,halo(C₁-C₆)alkenyl, phenyl, phenyl(C₁-C₆)alkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, indolyl, indazolyl, pyridinyl, pyrazolyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, indolylmethyl, pyridinylmethyl,pyrimidinylmethyl, pyrazinylmethyl, pyrazolylmethyl,tetrahydrofuranylmethyl, and pyridinylethyl; and when R¹ is(C₁-C₆)alkyl, then R² is selected from the group consisting of(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, phenyl,phenyl(C₁-C₆)alkyl, pyrazinylmethyl, and pyridinylmethyl; whereincyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherever theyoccur, are optionally substituted with one or more substituents selectedfrom the group consisting of hydroxy(C₁-C₆)alkyl, phenyl,phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino; and wherein when R¹is hydrogen and R² is cyclobutyl, then the cyclobutyl is substitutedwith one or more substituents selected from the group consisting ofhydroxy(C₁-C₆)alkyl, phenyl, phenyl(C₁-C₆)alkyl, and(C₁-C₆)alkoxycarbonylamino; wherein phenyl, wherever it occurs, isoptionally substituted with one or more substituents independentlyselected from the group consisting of cyano, halo, hydroxy,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl, (C₁-C₆)alkoxy, andaminosulfonyl; wherein indolyl, indazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyrazolyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, andtetrahydrofuranyl, wherever they occur, are optionally substituted withone or more substituents independently selected from the groupconsisting of halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, and amino; and whereinthe (C₁-C₆)alkyl in phenyl(C₁-C₆)alkyl is optionally substituted withone more substituents independently selected from the group consistingof halo and hydroxy; and R³ selected from the group consisting ofhydrogen and (C₁-C₆)alkyl.
 3. The compound of claim 1, wherein R¹ ishydrogen; R² is selected from the group consisting of (C₅-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₅-C₆)alkyl,(C₁-C₆)alkenyl, and halo(C₁-C₆)alkenyl; wherein the (C₃-C₆)cycloalkyl in(C₃-C₆)cycloalkyl(C₁-C₆)alkyl is optionally substituted with one or moresubstituents selected from the group consisting of hydroxy(C₁-C₆)alkyl,phenyl, halophenyl, phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino;and R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.4. The compound of claim 3, wherein R¹ is hydrogen; R² is selected fromthe group consisting of (C₅-C₆)alkyl, halo(C₁-C₆)alkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₅-C₆)alkyl, (C₁-C₆)alkenyl, andhalo(C₁-C₆)alkenyl; wherein the (C₃-C₆)cycloalkyl in(C₃-C₆)cycloalkyl(C₁-C₆)alkyl is optionally substituted with one or moresubstituents selected from the group consisting of hydroxy(C₁-C₆)alkyl,phenyl, halophenyl, phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino;and R³ selected from the group consisting of hydrogen and methyl.
 5. Thecompound of claim 4, wherein R¹ is hydrogen; R² is selected from thegroup consisting of cyclopropylmethyl and trifluorobutenyl; and R³selected from the group consisting of hydrogen and methyl.
 6. Thecompound of claim 1, wherein R¹ is (C₁-C₆)alkyl; R² is selected from thegroup consisting of (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkenyl, andhalo(C₁-C₆)alkenyl; wherein the (C₃-C₆)cycloalkyl in(C₃-C₆)cycloalkyl(C₁-C₆)alkyl is optionally substituted with one or moresubstituents selected from the group consisting of hydroxy(C₁-C₆)alkyl,phenyl, halophenyl, phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino;and R³ selected from the group consisting of hydrogen and (C₁-C₆)alkyl.7. The compound of claim 6, wherein R¹ is (C₁-C₆)alkyl; R² is selectedfrom the group consisting of (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, and hydroxy(C₁-C₆)alkyl; wherein the(C₃-C₆)cycloalkyl in (C₃-C₆)cycloalkyl(C₁-C₆)alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of hydroxy(C₁-C₆)alkyl, phenyl, halophenyl,phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino; and R³ selected fromthe group consisting of hydrogen and methyl.
 8. The compound of claim 6,wherein R¹ is (C₁-C₆)alkyl; R² is selected from the group consisting of(C₁-C₆)alkyl and hydroxy(C₁-C₆)alkyl; and R³ selected from the groupconsisting of hydrogen and (C₁-C₆)alkyl.
 9. The compound of claim 6,wherein R¹ is methyl; R² is selected from the group consisting of methyland hydroxyethyl; and R³ selected from the group consisting of hydrogenand methyl.
 10. The compound of claim 1, wherein R¹ is selected from thegroup consisting of hydrogen and (C₁-C₆)alkyl; and R² is selected fromthe group consisting of cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl; wherein cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexylare optionally substituted with one or more substituents selected fromthe group consisting of hydroxy(C₁-C₆)alkyl, phenyl, halophenyl,phenyl(C₁-C₆)alkyl, and (C₁-C₆)alkoxycarbonylamino; and wherein when R¹is hydrogen and R² is cyclobutyl, then the cyclobutyl is substitutedwith one or more substituents selected from the group consisting ofhydroxy(C₁-C₆)alkyl, phenyl, halophenyl, phenyl(C₁-C₆)alkyl, and(C₁-C₆)alkoxycarbonylamino; and R³ selected from the group consisting ofhydrogen and (C₁-C₆)alkyl.
 11. The compound of claim 10, wherein R¹ isselected from the group consisting of hydrogen and (C₁-C₆)alkyl; and R²is selected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl; wherein cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl are optionally substituted with one or moresubstituents selected from the group consisting of hydroxypropyl,phenyl, fluorophenyl, phenylmethyl and tert-butoxycarbonylamino; andwherein when R¹ is hydrogen and R² is cyclobutyl, then the cyclobutyl issubstituted with one or more substituents selected from the groupconsisting of hydroxypropyl, phenyl, fluorophenyl, phenylmethyl andtert-butoxycarbonylamino; and R³ selected from the group consisting ofhydrogen and (C₁-C₆)alkyl.
 12. The compound of claim 11, wherein R¹ ishydrogen.
 13. The compound of claim 11, wherein R¹ is (C₁-C₆)alkyl. 14.The compound of claim 11, wherein R¹ is selected from the groupconsisting of hydrogen and methyl; and R² is selected from the groupconsisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;wherein cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl areoptionally substituted with one or more substituents selected from thegroup consisting of hydroxypropyl, phenyl, fluorophenyl, phenylmethyland tert-butoxycarbonylamino; and wherein when R¹ is hydrogen and R² iscyclobutyl, then the cyclobutyl is substituted with one or moresubstituents selected from the group consisting of hydroxypropyl,phenyl, fluorophenyl, phenylmethyl and tert-butoxycarbonylamino; and R³selected from the group consisting of hydrogen and methyl.
 15. Thecompound of claim 11, wherein R¹ is hydrogen; R² is selected from thegroup consisting of cyclopropyl, fluorophenylcyclopentyl,hydroxypropylcyclohexyl, and tert-butoxycarbonylaminocyclobutyl; and R³selected from the group consisting of hydrogen and methyl.
 16. Thecompound of claim 1, wherein R¹ is selected from the group consisting ofhydrogen and (C₁-C₆)alkyl; R² is selected from the group consisting ofphenyl, phenyl(C₁-C₆)alkyl, heterocyclyl, and heterocyclyl(C₁-C₆)alkyl;and wherein phenyl, wherever it occurs, is optionally substituted withone or more substituents independently selected from the groupconsisting of cyano, halo, hydroxy, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,cyano(C₁-C₆)alkyl, (C₁-C₆)alkoxy, and aminosulfonyl; whereinheterocyclyl, wherever it occurs, is optionally substituted with one ormore substituents independently selected from the group consisting ofhalo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, and amino; and wherein the(C₁-C₆)alkyl in phenyl(C₁-C₆)alkyl and heterocyclyl(C₁-C₆)alkyl isoptionally substituted with one more substituents independently selectedfrom the group consisting of halo and hydroxy; and R³ selected from thegroup consisting of hydrogen and (C₁-C₆)alkyl.
 17. The compound of claim16, wherein R¹ is selected from the group consisting of hydrogen and(C₁-C₆)alkyl; R² is selected from the group consisting of phenyl andphenyl(C₁-C₆)alkyl; and wherein phenyl, wherever it occurs, isoptionally substituted with one or more substituents independentlyselected from the group consisting of cyano, halo, hydroxy;(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl, (C₁-C₆)alkoxy, andaminosulfonyl; and wherein the (C₁-C₆)alkyl in phenyl(C₁-C₆)alkyl isoptionally substituted with one more substituents independently selectedfrom the group consisting of halo and hydroxy; and R³ selected from thegroup consisting of hydrogen and (C₁-C₆)alkyl.
 18. The compound of claim17, wherein R¹ is selected from the group consisting of hydrogen and(C₁-C₆)alkyl; R² is selected from the group consisting of phenyl andphenyl(C₁-C₄)alkyl; wherein phenyl, wherever it occurs, is optionallysubstituted with one or more substituents independently selected fromthe group consisting of cyano, chloro, fluoro, hydroxy, methyl,trifluoromethyl, cyanomethyl, methoxy, and aminosulfonyl; and whereinthe (C₁-C₄)alkyl in phenyl(C₁-C₄)alkyl is optionally substituted withone more substituents independently selected from the group consistingof fluoro and hydroxy; and R³ is selected from the group consisting ofhydrogen and methyl.
 19. The compound of claim 18, wherein R¹ isselected from the group consisting of hydrogen and methyl; R² isselected from the group consisting of phenyl and phenyl(C₁-C₄)alkyl;wherein phenyl, wherever it occurs, is optionally substituted with oneor more substituents independently selected from the group consisting ofcyano, chloro, fluoro, hydroxy, methyl, trifluoromethyl, cyanomethyl,methoxy, and aminosulfonyl; and wherein the (C₁-C₄)alkyl inphenyl(C₁-C₄)alkyl is optionally substituted with one more substituentsindependently selected from the group consisting of fluoro and hydroxy;and R³ is selected from the group consisting of hydrogen and methyl. 20.The compound of claim 16, wherein R¹ is selected from the groupconsisting of hydrogen and (C₁-C₆)alkyl; R² is selected from the groupconsisting of heterocyclyl and heterocyclyl(C₁-C₆)alkyl; and whereinheterocyclyl, wherever it occurs, is optionally substituted with one ormore substituents independently selected from the group consisting ofhalo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, and amino; and wherein the(C₁-C₆)alkyl in heterocyclyl(C₁-C₆)alkyl is optionally substituted withone more substituents independently selected from the group consistingof halo and hydroxy; and R³ selected from the group consisting ofhydrogen and (C₁-C₆)alkyl.
 21. The compound of claim 20, wherein R¹ isselected from the group consisting of hydrogen and (C₁-C₆)alkyl; R² isselected from the group consisting of 3-12 membered ring heterocyclyland 3-12 membered ring heterocyclyl(C₁-C₆)alkyl; and whereinheterocyclyl, wherever it occurs, is optionally substituted with one ormore substituents independently selected from the group consisting ofhalo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, and amino; and wherein the(C₁-C₆)alkyl in heterocyclyl(C₁-C₆)alkyl is optionally substituted withone more substituents independently selected from the group consistingof halo and hydroxy; and R³ selected from the group consisting ofhydrogen and (C₁-C₆)alkyl.
 22. The compound of claim 21, wherein R¹ isselected from the group consisting of hydrogen and (C₁-C₆)alkyl; R² isselected from the group consisting of indolyl, indazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyrazolyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, tetrahydrofuranyl,indolyl(C₁-C₆)alkyl, indazolyl(C₁-C₆)alkyl, pyridinyl(C₁-C₆)alkyl,pyrimidinyl(C₁-C₆)alkyl, pyrazinyl(C₁-C₆)alkyl, pyrazolyl(C₁-C₆)alkyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl(C₁-C₆)alkyl, andtetrahydrofuranyl(C₁-C₆)alkyl; and wherein indolyl, indazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, tetrahydrofuranyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, and amino;and wherein the (C₁-C₆)alkyl in indolyl(C₁-C₆)alkyl,indazolyl(C₁-C₆)alkyl, pyridinyl(C₁-C₆)alkyl, pyrimidinyl(C₁-C₆)alkyl,pyrazinyl(C₁-C₆)alkyl, pyrazolyl(C₁-C₆)alkyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl(C₁-C₆)alkyl, andtetrahydrofuranyl(C₁-C₆)alkyl is optionally substituted with one moresubstituents independently selected from the group consisting of haloand hydroxy; and R³ selected from the group consisting of hydrogen and(C₁-C₆)alkyl.
 23. The compound of claim 21, wherein R¹ is selected fromthe group consisting of hydrogen and (C₁-C₆)alkyl; R² is selected fromthe group consisting of indolyl, indazolyl, pyridinyl, pyrazolyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, indolylmethyl, pyridinylmethyl,pyrimidinylmethyl, pyrazinylmethyl, pyrazolylmethyl,tetrahydrofuranylmethyl, and pyridinylethyl; and wherein indolyl,indazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, and tetrahydrofuranyl areoptionally substituted with one or more substituents independentlyselected from the group consisting of halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,and amino; and R³ selected from the group consisting of hydrogen and(C₁-C₆)alkyl.
 24. The compound of claim 23, wherein R¹ is selected fromthe group consisting of hydrogen and methyl; R² is selected from thegroup consisting of indolyl, indazolyl, pyridinyl, pyrazolyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, indolylmethyl, pyridinylmethyl,pyrimidinylmethyl, pyrazinylmethyl, pyrazolylmethyl,tetrahydrofuranylmethyl, and pyridinylethyl; wherein indolyl, indazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, and tetrahydrofuranyl, areoptionally substituted with one or more substituents independentlyselected from the group consisting of chloro, methyl, methoxy, andamino; and R³ selected from the group consisting of hydrogen and methyl.25. The compound of claim 1, wherein the compound is selected from thegroup consisting of:N-(cyclopropylmethyl)-1-{cis-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-(3,4,4-trifluorobut-3-en-1-yl)methanesulfonamide;N-(2-hydroxyethyl)-N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[(6-aminopyridin-2-yl)methyl]-N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-(pyridin-3-ylmethyl)methanesulfonamide;N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-(pyrazin-2-ylmethyl)methanesulfonamide;N,N-dimethyl((1r,4r)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide;N-cyclopropyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[trans-4-(1-hydroxy-1-methylethyl)cyclohexyl]-1-{trans-4-[(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;tert-butyl(3-{[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methyl)sulfonyl]amino}cyclobutyl)carbamate;N-[(1R,2R)-2-(4-fluorophenyl)cyclopentyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-(1-benzylcyclobutyl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-[(1S,2R)-2-phenylcyclopropyl]methanesulfonamide;-(2-{[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methyl)sulfonyl]amino}ethyl)benzenesulfonamide;N-[2-(4-hydroxyphenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[2-(2,4-dimethylphenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[2-(2-methoxyphenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-(2,2-difluoro-2-phenylethyl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[2-(4-methylphenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[2-fluoro-2-(4-fluorophenyl)propyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[2-fluoro-2-(3-fluorophenyl)propyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[2-(3-methoxyphenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[2-fluoro-2-(4-fluorophenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-{2-[4-(trifluoromethyl)phenyl]ethyl}methanesulfonamide;N-{2-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl}-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-(2-phenylethyl)methanesulfonamide;N-benzyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-(4-methoxybenzyl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[4-(cyanomethyl)phenyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-(4-cyanophenyl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[2-(4-chlorophenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[2-(2-fluorophenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[2-(3-fluorophenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[2-(3-chlorophenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[2-(2-fluoro-4-isopropylphenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[2-(3,4-difluorophenyl)-2-hydroxyethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[3-(2-methoxyphenyl)propyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[2-(3,4-dichlorophenyl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;1-{cis-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-(2-phenylethyl)methanesulfonamide;N-benzyl-1-{cis-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-(4-methoxybenzyl)-1-{cis-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-(pyridin-3-ylmethyl)methanesulfonamide;1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-1H-pyrazol-5-ylmethanesulfonamide;N-(5-methyl-1H-pyrazol-3-yl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-1H-indol-5-yl-1-{trans-4-[(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-(6-chloropyridin-3-yl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-1H-indazol-5-yl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-(6-methoxypyridin-3-yl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-(6-methylpyridin-3-yl)-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[(2-methyl-1H-indol-5-yl)methyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[(5-methylpyrazin-2-yl)methyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-N-[(2R)-tetrahydrofuran-2-ylmethyl]methanesulfonamide;N-[2-(6-methylpyridin-2-yl)ethyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;N-[(4,6-dimethylpyrimidin-2-yl)methyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;andN-[(1,3-dimethyl-1H-pyrazol-4-yl)methyl]-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide;or a pharmaceutically acceptable salt thereof.
 26. A pharmaceuticalcomposition comprising a compound of Formula I or a pharmaceuticallyacceptable salt thereof.
 27. A method for the treatment of a JanusKinase mediated condition in a subject in need of such treatment,wherein the method comprises administering to the subject an amount of acompound of Formula I or a pharmaceutically acceptable salt thereof,wherein the amount of the compound is effective for the treatment of theJanus Kinase mediated condition.
 28. The method of claim 27, wherein theJanus Kinase mediated condition is Alzheimer's disease, arthritisautoimmune thyroid disorders, cancer, diabetes, leukemia, T-cellprolymphocytic leukemia, lymphoma, myleoproliferation disorders, lupus,multiple myeloma, multiple sclerosis, osteoarthritis, sepsis, prostatecancer, T-cell autoimmune disease, inflammatory diseases, chronic andacute allograft transplant rejection, bone marrow transplant, stroke,asthma, chronic obstructive pulmonary disease, allergy, bronchitis,viral diseases, or Type I diabetes and complications from diabetes. 29.The method of claim 27 wherein the Janus Kinase mediated condition isselected from the group consisting of asthma, Crohn's disease, dry eye,uveitis, inflammatory bowel disease, organ transplant rejection,psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosingspondylitis and ulcerative colitis.